The intramolecular Friedel-Crafts acylation of aromatics with Meldrum?s acid derivatives catalyzed by metal trifluoromethanesulfonates and other Lewis acids is reported. Meldrum?s acids are easily prepared, functionalized, handled, and purified. The synthesis of polysubstituted 1-indanones from benzyl Meldrum's acids was investigated thoroughly, and it was shown that a variety of catalysts were effective, whilst accommodating a diversity of functional groups under mild conditions. The scope, limitations, and functional group tolerance (terminal alkene and alkyne, ketal, dialkyl ether, dialkyl thioether, aryl methyl ether, aryl TIPS and TBDPS ethers, nitrile- and nitro-substituted aryls, alkyl and aryl halides) for a variety of 5-benzyl (enolizable Meldrum?s acids) and 5-benzyl-5-substituted Meldrum?s acids (quaternarized Meldrum?s acids), forming 1-indanones and 2-substituted-1-indanones respectively, are delineated. <br ><br /> This method was further applied to the synthesis of 1-tetralones, 1-benzosuberones, and the potent acetylcholinesterase inhibitor donepezil. <br ><br /> Mechanistic investigations were undertaken to determine the rate-determining step in the acylation sequence using Meldrum?s acid, as well as to examine the role of the Lewis acid catalyst. Enolizable Meldrum?s acid derivatives can react via an acyl ketene intermediate under thermal conditions, while quaternarized Meldrum?s acid derivatives are thermally stable and only act as effective Friedel-Crafts acylating agents in the presence of a Lewis acid catalyst. <br ><br /> The total synthesis of (??)-Taiwaniaquinol B was completed. This natural product was the first ever isolated containing an unusual 6-5-6 fused ring system, and it also contains a hexasubstituted aromatic ring, and two all-carbon quaternary centers. This synthesis was accomplished via an intramolecular Friedel-Crafts acylation/carbonyl a-<em>tert</em>-alkylation reaction that exploits the unique chemistry of Meldrum?s acid. This novel methodology can be used to access a variety of highly substituted fused ring systems of various sizes.

The intramolecular Friedel-Crafts acylation of aromatics with Meldrum?s acid derivatives catalyzed by metal trifluoromethanesulfonates and other Lewis acids is reported. Meldrum?s acids are easily prepared, functionalized, handled, and purified. The synthesis of polysubstituted 1-indanones from benzyl Meldrum's acids was investigated thoroughly, and it was shown that a variety of catalysts were effective, whilst accommodating a diversity of functional groups under mild conditions. The scope, limitations, and functional group tolerance (terminal alkene and alkyne, ketal, dialkyl ether, dialkyl thioether, aryl methyl ether, aryl TIPS and TBDPS ethers, nitrile- and nitro-substituted aryls, alkyl and aryl halides) for a variety of 5-benzyl (enolizable Meldrum?s acids) and 5-benzyl-5-substituted Meldrum?s acids (quaternarized Meldrum?s acids), forming 1-indanones and 2-substituted-1-indanones respectively, are delineated. <br ><br /> This method was further applied to the synthesis of 1-tetralones, 1-benzosuberones, and the potent acetylcholinesterase inhibitor donepezil. <br ><br /> Mechanistic investigations were undertaken to determine the rate-determining step in the acylation sequence using Meldrum?s acid, as well as to examine the role of the Lewis acid catalyst. Enolizable Meldrum?s acid derivatives can react via an acyl ketene intermediate under thermal conditions, while quaternarized Meldrum?s acid derivatives are thermally stable and only act as effective Friedel-Crafts acylating agents in the presence of a Lewis acid catalyst. <br ><br /> The total synthesis of (±)-Taiwaniaquinol B was completed. This natural product was the first ever isolated containing an unusual 6-5-6 fused ring system, and it also contains a hexasubstituted aromatic ring, and two all-carbon quaternary centers. This synthesis was accomplished via an intramolecular Friedel-Crafts acylation/carbonyl a-<em>tert</em>-alkylation reaction that exploits the unique chemistry of Meldrum?s acid. This novel methodology can be used to access a variety of highly substituted fused ring systems of various sizes.

Les deux objectifs principaux de cette thèse sont : la préparation de nouvelles cétones insaturées et l'étude de leurs propriétés dans les domaines biologiques et de la chimie des matériaux. La synthèse de nouveaux bis-ylures mixtes-(P,S) et l'étude de leur réactivité. Dans le premier chapitre, après une introduction bibliographique sur l'importance des cétones a,b-insaturées dans le domaine biologique, sont décrites les synthèses de nouvelles dichalcones et d'hydroxybenzylidène-indanones. Le deuxième chapitre est consacré à l'étude de la chimie de coordination des nouveaux composés préparés, avec un intérêt particulier pour les complexes de fer(0) pour les bis-chalcones et de fer(III) pour les hydroxybenzylidène-indanones. Quelques complexes de cuivre(II) et de vanadium(V) sont également décrits. Le troisième chapitre est dédié à l'utilisation des composés organiques et complexes organométalliques dans le domaine de la biologie, et plus particulièrement leur activité cytotoxique. Des résultats très encourageants ont été obtenus notamment comme anti-cancéreux potentiel contre les lignées cellulaires U-251 (glioblastome). Les complexes d'hydroxybenzylidène-indanones de fer(III) ont également été utilisés pour préparer des films minces présentant des propriétés intéressantes en tant que semi-conducteurs. La dernière partie de ce manuscrit de thèse contient un rappel sur la chimie des bis-ylures et leur potentiel en tant que source de carbone atomique. Il décrit ensuite la synthèse, la caractérisation et la réactivité de deux nouveaux modèles de bis-ylures mixtes-(P,S). / The present work concerns two main topics: the development of new unsaturated ketones and the study of their properties towards biological and material applications. The preparation of new (P,S)-bis-ylides, species that can behave as atomic carbon source. In the first chapter, a brief bibliographic overview describes the importance of unsaturated ketones for biological applications followed by the synthesis and characterization of new bis-chalcones and hydroxybenzylidene-indanones. The second chapter deals with the preparation of new organometallic complexes, more specifically new bis-chalcones iron(0) complexes and new hydroxybenzylidene-indanone iron(III) complexes. Most of these species have been characterized by X-Ray diffraction analysis. Some copper(II) and vanadium(V) are also described. The third chapter is dedicated to the study of the new organic and organometallic compounds towards applications in biology and materials science. Of special interest, hydroxybenzylidene-indanone iron(III) complexes exhibits excellent results as cytotoxic agents for U-251 cancer cells (glioblastome). In addition, some of the complexes synthesized are useful to prepare thins film displaying semi-conductor properties. The last chapter of this manuscript contains an overview on bis-ylide chemistry, more specifically towards the species that can behave as sources of elementary carbon. Then the synthesis, characterization and reactivity of two new (P,S)-bis-ylides are described.

<p>In medicinal chemistry, there is a constant need for new preparative methods, both to make the synthesis process more effective, and to increase the accessibility to a wide variety of compounds. A number of different approaches can be used to attain these goals. Transition metal catalysis is generally performed under mild conditions, providing both regio- and chemoselective reactions. Thus, it offers an attractive means of preparation of complex drug candidates. Two additional methodologies used to increase the preparative efficiency are one-pot protocols and controlled microwave heating. One-pot and multi-component reactions are less time consuming than step-by-step reactions, and microwave heating has been used to considerably shorten the reaction times. </p><p>This thesis describes a new palladium-catalyzed, one-pot reaction producing racemic acetal-protected 3-hydroxy-1-indanones from ethylene glycol vinyl ether and triflates of salicylic aldehydes. The triflates were prepared using controlled microwave heating. The reaction sequence starts with a regioselective internal Heck coupling, followed by an annulation cascade. By including secondary amines in the reaction mixture, the reaction was further developed into a three-component reaction delivering racemic acetal-protected 3-amino-1-indanones. This new method was utilized for the synthesis of primary, secondary and tertiary aminoindanones. Finally, by using enantiopure t-butyl sulfinyl imines, derived from salicylic aldehyde triflates and ethylene glycol vinyl ether as starting materials in a closely related type of palladium coupling–annulation sequence, a stereoselective protocol providing enantiomerically pure 3-amino-1-indanones was developed. To demonstrate an application in medicinal chemistry, the enantiopure 3-amino-1-indanones were incorporated as P2 and/or P2´ substituents into active HIV-1 protease inhibitors.</p>

In medicinal chemistry, there is a constant need for new preparative methods, both to make the synthesis process more effective, and to increase the accessibility to a wide variety of compounds. A number of different approaches can be used to attain these goals. Transition metal catalysis is generally performed under mild conditions, providing both regio- and chemoselective reactions. Thus, it offers an attractive means of preparation of complex drug candidates. Two additional methodologies used to increase the preparative efficiency are one-pot protocols and controlled microwave heating. One-pot and multi-component reactions are less time consuming than step-by-step reactions, and microwave heating has been used to considerably shorten the reaction times. This thesis describes a new palladium-catalyzed, one-pot reaction producing racemic acetal-protected 3-hydroxy-1-indanones from ethylene glycol vinyl ether and triflates of salicylic aldehydes. The triflates were prepared using controlled microwave heating. The reaction sequence starts with a regioselective internal Heck coupling, followed by an annulation cascade. By including secondary amines in the reaction mixture, the reaction was further developed into a three-component reaction delivering racemic acetal-protected 3-amino-1-indanones. This new method was utilized for the synthesis of primary, secondary and tertiary aminoindanones. Finally, by using enantiopure t-butyl sulfinyl imines, derived from salicylic aldehyde triflates and ethylene glycol vinyl ether as starting materials in a closely related type of palladium coupling–annulation sequence, a stereoselective protocol providing enantiomerically pure 3-amino-1-indanones was developed. To demonstrate an application in medicinal chemistry, the enantiopure 3-amino-1-indanones were incorporated as P2 and/or P2´ substituents into active HIV-1 protease inhibitors.