Synthèse générale des noyaux spiranniques Au cours de ce travail, nous avons développé une méthode générale permettant d'assembler rapidement les noyaux spiro[4,4+n]alcanones (5) et spiro[5,4+n]alcanones (6). Durant l'étape de condensation, les ß-cétocétals (4) et (7) ont été obtenus avec de bons rendements grâce à l'emploi de dichlorure de zinc comme acide de Lewis. Différentes bases ont été testées dans l'étape de spiroannélation. Les meilleurs résultats ont été obtenus en utilisant du tert-butanolate de potassium dans le THF en présence d'un équivalent d'eau. La sélectivité de notre méthodologie a également été examinée lors de la génération des composés spiranniques substitués (10), (11), (13) et (15). Durant cette étude, nous avons notamment montré que la condensation et la cyclisation sont complètement diastéréosélectives au départ des éthers d'énols silylés (12) et des orthoesters (2) et (3). Applications En utilisant notre séquence réactionnelle, nous avons synthétisé la spirocétone (18). La fonctionnalisation de ce dérivé spirannique (18), nous a conduit à l'intermédiaire (19) qui pourrait être ultérieurement utilisé pour la synthèse de produits naturels tel que (20), appartenant à la classe des spirovétivanes La spirodicétone (23) a été employée dans la synthèse total de l'Erythrodiène (24) et du Spirojatamol (25) par Fukumoto. Notre méthodologie nous a permis de générer cet intermédiaire clef (23) en seulement trois étapes.

For the past years, our laboratory has been interested in the development of a specific class of functionalised orthoester derivatives and their application as annelating reagents. Previous work had demonstrated that these reagents could be used in a two-step procedure to generate interesting spirocyclic ketones. At the onset of our thesis, we devoted our efforts to the study and application of this methodology. This resulted in an improved and more efficient procedure for the spirohexannelation of â-ketoketals. During these initial studies, an intriguing and novel transannular cyclisation was discovered. The reactivity of these spirocycles was also briefly examined, laying the ground for an application to the total synthesis of Agarospirol, Hinesol and á-Vetispirene, three natural products belonging to the Spirovetivane family. The applicability of a CAN-catalysed deprotection of ketals and silyl ethers, in the presence of an enol triflate moiety, was also investigated. The potential of our functionalised orthoesters as annelating agents was then further evaluated in the context of other silyl enolethers. The heteroaromatic derivatives of furan proved to be excellent coupling partners for our functionalised orthoesters, and enabled the efficient preparation of a wide array of butenolides. These butenolides could then be elaborated, by an efficient and highly stereoselective radical-mediated cyclisation, into bicyclic lactones. Alternatively, treatment with base triggered an efficient spirocyclisation, delivering spirocyclic butenolides in good to excellent yields. The corresponding pyrrole derivative was also examinated, and preliminary work hints at the possibility of readily preparing azaspirocycles as well as indolizidine frameworks. Finally, the evaluation of silylated acyloins allowed an entry into the chemistry of cyclobutanones, and a simple procedure for the synthesis of spirocyclic ethers was developed. During these investigations, an unexpected fragmentation was serendipitously discovered upon application of the Beckmann rearrangement. We were able to use this reaction in a new procedure for the synthesis of interestingly substituted tetrahydropyrans.

Cyclooctyne and cycloocten-5-yne undergo, at room temperature, a 1,3-dipolar cycloaddition with dialkyl acetylenedicarboxylates 1a,b to generate furan-derived short-lived intermediates 2, which can be trapped by two additional equivalents of 1a,b or alternatively by methanol, phenol, water or aldehydes to yield polycyclic products 3b–d, orthoesters 4a–c, ketones 5 or epoxides 6a,b, respectively. Treatment of bis(trimethylsilyl) acetylenedicarboxylate (1c) with cyclooctyne leads to the ketone 7 via retro-Brook rearrangement of the dipolar intermediate 2c. In all cases, the products are formed with perfect atom economy.

Cyclooctyne and cycloocten-5-yne undergo, at room temperature, a 1,3-dipolar cycloaddition with dialkyl acetylenedicarboxylates 1a,b to generate furan-derived short-lived intermediates 2, which can be trapped by two additional equivalents of 1a,b or alternatively by methanol, phenol, water or aldehydes to yield polycyclic products 3b–d, orthoesters 4a–c, ketones 5 or epoxides 6a,b, respectively. Treatment of bis(trimethylsilyl) acetylenedicarboxylate (1c) with cyclooctyne leads to the ketone 7 via retro-Brook rearrangement of the dipolar intermediate 2c. In all cases, the products are formed with perfect atom economy.