Thesis--Wisconsin. / Vita. Includes bibliographical references.

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Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

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Les composés oxygénés de faible poids moléculaire présentent un fort intérêt en chimie des parfums. Un grand nombre d’odorants contiennent un ou plusieurs cycles au sein de leur structure. Ce travail de thèse est dédié au développement de nouvelles carbocyclisations intramoléculaires de dérivés d’éthers d’énol catalysées par des (super)acides de Lewis. L’étude s’intéresse à la réactivité bivalente des alcools (bis)allyliques portant une fonction alkoxy. Dans ce contexte, la réactivité de la fonction éther d’énol en présence d’un alcool allylique a été développée en présence d’acides de Lewis et de Brønsted comme catalyseurs. En l’occurrence, une chimiodivergence contrôlée par le substrat a été démontrée pour des précurseurs dérivés de différents types d’éthers d’énol. Ainsi, des cyclopenténones ont été formées par électrocyclisation catalysée par le triflate de bismuth(III). Ou alors, des cétones insaturées α-oxygénées ou soufrées ont été obtenues par activation préferentielle de l’éther d’énol en présence de l’acide ptoluènesulfonique. Une étude mécanistique a été effectuée mettant en avant la différence entre la catalyse par acides de Lewis et de Brønsted ainsi que l’influence de l’acidité du catalyseur. Il a été possible de contrôler la chimiodivergence par le catalyseur dans le cas des dérivés du phenyl vinyl sulfure. Deux produits différents ont été obtenus à partir d’un seul substrat de départ en utilisant des systèmes catalytiques robustes et peu onéreux. La plupart des nouveaux composés présentent des notes olfactives intéressantes. En outre, l’électrocyclisation catalysée par le triflate de bismuth a été appliquée à la synthèse de la rotundone, un odorant naturel à la note typique du poivre. / Oxygenated low molecular weight compounds are of particular interest in fragrance chemistry. A large number of odorants present one or more rings within their structure. This work is dedicated to the development of novel intramolecular carbocyclizations of enol ether derivatives catalyzed by Lewis (super)acids. The study turns around the dual reactivity of alkoxy-substituted bis(allylic) alcohols. In this context, the behavior of the enol ether function in the presence of an allylic alcohol has been elaborated under Lewis and Brønsted acid-catalysis. Hereby, a pronounced substrate-controlled chemodivergence as demonstrated for precursors derived from different types of enol ethers. Either, cyclopentenones were formed by electrocyclization under bismuthIII triflate catalysis, or a skeletal rearrangement after preferential activation of the enol ether in the presence of p-toluenesulfonic led to α-oxygenated or αsulfenylated unsaturated ketones. Mechanistic studies have been performed and the difference between Lewis and Brønsted acid-catalysis as well as the influence of the catalyst acidity have been highlighted. The chemodivergence could be tuned by the nature of the catalyst in the case of phenyl vinyl sulfide derivatives. Two different products were obtained from a single and easily accessible starting material using robust, air- and water-compatible catalytic systems. Most of the new compounds presented interesting olfactory notes. The developed bismuthIII triflate-catalyzed electrocyclization was further applied to the total synthesis of the natural pepper odorant rotundone.

<p>The usefulness of low concentrations (typically 10 to 100 <i>µ</i>M) of [¹¹C]carbon monoxide and aryl triflates as substrates in ¹¹C-carbonylation using different nucleophiles in the presence of lithium bromide was investigated. The reactions were performed in a micro autoclave of 200 <i>µ</i>L volume and catalysed (mediated) by palladium(0). </p><p>A peripheral type benzodiazepine receptor (PBR) ligand, 1-(2-chlorophenyl)-<i>N</i>-methyl-<i>N</i>-(1-methylpropyl)isoquinoline-3-carboxamide (PK11195) and its structural analogues including an irreversible ligand for PBR, some other amides, ketones and carboxylic acids, were all labelled with ¹¹C using this approach. The [<i>carbonyl</i>-¹¹C]PK11195, analogues and other amides were prepared from aryl triflates and amines, and the [<i>carbonyl</i>-¹¹C]ketones were prepared from aryl triflates and organoboranes. In the synthesis of [<i>carboxyl</i>-¹¹C]carboxylic acids, water was utilised as nucleophile. The decay-corrected radiochemical yields were 10 to 55% for [¹¹C]PK11195 and analogues, 2 to 63% for other [¹¹C]amides, 10 to 75% for [¹¹C]ketones and 25 to 65% for [¹¹C]carboxylic acids. The specific radioactivity of the labelled compounds was in the range of 150 to 900 GBq/<i>µ</i>mol. </p><p>Some [¹¹C]amines were prepared by a reductive amination of the corresponding [carbonyl-¹¹C]ketones. These reactions were performed using different amines in the presence of TiCl₄ and NaBH₃CN. The radiochemical yields of the [¹¹C]amines varied from 2 to 78% (determined by analytical HPLC). </p><p>In order to confirm the labelling position, synthesis of selected ¹³C-substituted compounds were performed. For each substance group/ synthesis method, a selected compound was synthesised using (¹³C)carbon monoxide and the ¹³C-substituted compound was then analysed by ¹³C NMR.</p><p>A synthetic route was developed for the preparation of 1-(2-chloro-phenyl)-isoquinolin-3-yl trifluoromethanesulfonate used as the precursor in the synthesis of [<i>carbonyl</i>-¹¹C]PK11195 and analogues.</p>

The usefulness of low concentrations (typically 10 to 100 µM) of [11C]carbon monoxide and aryl triflates as substrates in 11C-carbonylation using different nucleophiles in the presence of lithium bromide was investigated. The reactions were performed in a micro autoclave of 200 µL volume and catalysed (mediated) by palladium(0). A peripheral type benzodiazepine receptor (PBR) ligand, 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)isoquinoline-3-carboxamide (PK11195) and its structural analogues including an irreversible ligand for PBR, some other amides, ketones and carboxylic acids, were all labelled with 11C using this approach. The [carbonyl-11C]PK11195, analogues and other amides were prepared from aryl triflates and amines, and the [carbonyl-11C]ketones were prepared from aryl triflates and organoboranes. In the synthesis of [carboxyl-11C]carboxylic acids, water was utilised as nucleophile. The decay-corrected radiochemical yields were 10 to 55% for [11C]PK11195 and analogues, 2 to 63% for other [11C]amides, 10 to 75% for [11C]ketones and 25 to 65% for [11C]carboxylic acids. The specific radioactivity of the labelled compounds was in the range of 150 to 900 GBq/µmol. Some [11C]amines were prepared by a reductive amination of the corresponding [carbonyl-11C]ketones. These reactions were performed using different amines in the presence of TiCl4 and NaBH3CN. The radiochemical yields of the [11C]amines varied from 2 to 78% (determined by analytical HPLC). In order to confirm the labelling position, synthesis of selected 13C-substituted compounds were performed. For each substance group/ synthesis method, a selected compound was synthesised using (13C)carbon monoxide and the 13C-substituted compound was then analysed by 13C NMR. A synthetic route was developed for the preparation of 1-(2-chloro-phenyl)-isoquinolin-3-yl trifluoromethanesulfonate used as the precursor in the synthesis of [carbonyl-11C]PK11195 and analogues.

Les éthers cycliques et les lactones représentent des cibles de choix pour la chimie des arômes et parfums. Dans ce contexte, l'objectif de ce travail de thèse concerne la mise au point d'un système catalytique permettant la cycloisomérisation d'alcools et d'acides insaturés, respectivement en éthers cycliques et en lactones.<br /><br />L'utilisation de superacides de Lewis de type triflates métalliques (Mn+(OTf)n) a permis l'élaboration d'un système catalytique faisant intervenir le triflate d'aluminium ou d'étain à 5% molaire dans le nitrométhane. <br /><br />Ce système catalytique a ensuite été appliqué à la synthèse de divers squelettes intéressant en chimie des arômes et parfums tels que les éthers spiranniques, les spirodilactones ainsi que les thioéthers cycliques et les thiolactones. Une synthèse originale de l'oxyde de rose et du Doremox® a également été proposée.<br /><br />En parallèle, l'introduction de ligands chiraux pouvant se coordinner au métal en vue de réaliser des cyclisations énantiosélectives a fait l'objet d'une étude qui est actuellement poursuivie au laboratoire.<br /><br />Enfin, une étude mécanistique faisant appel à des calculs théoriques semi-empiriques ainsi qu'à des analyses par RMN a permis de proposer une hypothèse de chemin réactionnel.

Ph.D. / The research contained in this thesis was aimed at the applications of Lewis acids (metal triflate salts in particular) and Brønsted acids as catalysts for various organic synthesis reactions. The ultimate objective was to prepare combinations of the Lewis and Brønsted acids to form assisted acids. The assisted acids yield to the formation of highly acidic assisted acids which exhibit high activity as compared to the individual Lewis and Brønsted acids. A detailed literature study was undertaken, with emphasis on the applications of metal triflate salts as catalysts for various organic reactions and the applications of assisted acids. The study was motivated by the fact that metal triflate Lewis acids are thermally stable, non corrosive and water tolerant catalysts, hence can be used industrially to replace the corrosive, moisture sensitive acids as catalysts. However, metal triflates have not yet been recognised and utilised in the chemical industry. On the other hand, the active Brønsted acids such as triflic acid, H2SO4 etc. are corrosive, which restricts the type of construction material to hastelloy. However, the assisted acids composed of less corrosive Brønsted acids and metal triflate Lewis acid is desirable to address the corrosion and safety challenges. The metal triflate salts and Brønsted acids were evaluated as catalysts for etherification reactions of alcohols and olefins, Friedel-Crafts alkylation reactions phenolic substrates with isobutylene. The study showed that some dependence of the charge density to the activity, i.e. metal triflate salts such as Al(OTf)3, Zr(OTf)4 and Sc(OTf)3 with relatively high charge density were more effective in catalysing the reactions than those with relatively smaller charge density such as lanthanides, which were virtually active. The activity of Brønsted acids showed a clear dependence on the acid strength pKa, with H3PO4 giving the least activity. The assisted acids formed via a combination of metal triflate salts with mineral Brønsted acids showed a significant enhancement of the reaction rates as compared to the individual acids. This set of new combined acids was proven to be excellent catalysts for the etherification reactions, Friedel-Crafts alkylation reactions and also for the synthesis of biologically active compounds called chromans. The assisted acids as well as Al(OTf)3, and Zr(OTf)4 could be recycled at least four times without significant loss of activity. The study also showed that assisted acids could be recycled for both etherification and Friedel-Crafts reactions.