La présence importante des hétérocycles azotés en chimie organique et médicinale explique le grand intérêt et les très nombreuses recherches dont ils font l’objet. Parmi tous ces motifs, les pyrrolidines ainsi que les γ- et δ-lactames bicycliques ont tout particulièrement focalisé notre attention. En se basant sur des résultats antérieurs obtenus au laboratoire nous avons mis au point deux nouvelles voies d’accès rapides et innovantes pour accéder diastéréosélectivement à ces motifs. D’une part une réaction tandem aza-MIRC (Michael Induced Ring Closure) a permis de former des pyrrolidines polysubstituées et d’autre part une séquence domino oxa-Michael/aza-MIRC a donné accès à de très nombreux γ- et δ-lactames bicycliques. Ces deux méthodes ont, en outre, été appliquées à la synthèse de composés d’intérêts connus pour leurs activités biologiques. La séquence aza-MIRC a été utilisée pour les synthèses totale et formelle respectivement des alcaloïdes Coerulescine et Martinelline, tandis que le processus oxa-Michael/aza-MIRC a été employé pour accéder de manière stéréosélective à des composés spirooxindoliques énantioenrichis. En parallèle du développement de ces deux méthodes, une étude mécanistique poussée de la séquence oxa-Michael/aza-MIRC a été réalisée au moyen de calculs théoriques. Cette étude a permis d’expliquer la majeure partie des résultats obtenus en fournissant un outil puissant capable d’anticiper, dans une certaine mesure, la réactivité de la séquence domino oxa-Michael/aza-MIRC. / N-heterocycle scaffolds are found in many synthetic and medicinal chemical compounds explaining the high interest for developing efficient synthetic methodologies to reach such structures. In that field, our group has developed over the years innovative routes to y-lactams and bicyclic γ- and δ-lactams using tandem and domino reactions. Based on those previous works, we have developed two new methods to synthesize N-heterocycles. A tandem aza-MIRC (Michael Induced Ring Closure) sequence have been investigated to access pyrrolidines whereas the bicyclique scaffold of bislactames have been obtained using a domino oxa-Michael/aza-MIRC pathway. These two new methods have been then applied to the syntheses of more complexes and thus challenging backbones. The aza-MIRC tandem process have been used for the total and formal synthesis of alkaloids Coerulescine and Martinelline, respectively, whereas the domino oxa-Michael/aza-MIRC sequence has proved to be a powerful tool for stereoselective access to enantioenriched spirooxindolic compounds. DFT calculations studies have allowed elucidation of the diastereoselectivity and double chirality transfer of the domino reaction therefore could be used in the future to develop efficient total syntheses.

This thesis is concerned with the application of the conjugate addition of enantiopure lithium amides in the asymmetric syntheses of (−)-martinellic acid. Chapter 1 introduces the importance of the quinoline motif in a wide variety of natural products and pharmaceuticals. The natural products (–)-martinellic acid and (+)-martinelline are introduced and previous methods for their synthesis are described. Chapter 2 introduces the conjugate addition reaction of lithium N-benzyl-N-α-methylbenzylamide as a means of synthesising β-amino esters from α,β-unsaturated esters. Both “tandem” and “stepwise” enolate functionalisation pathways to introduce an α-substituent are discussed, and the products are cyclised to the corresponding quinolin-2-ones. Modification of this strategy allowed the development of a double cyclisation reaction to form the pyrroloquinoline core found within (–)-martinellic acid and (+)-martinelline. Initial attempts at elaborating the tricyclic core to the natural products are described. Chapter 3 addresses the difficulties encountered in the initial synthetic route by the use of lithium (R)-N-allyl-N-(α-methyl-4-methoxy-benzyl)amide as an alternative enantiopure ammonia equivalent. A key Wittig and intramolecular Michael reaction is used to introduce the remaining stereogenic centre, allowing access to either epimeric series. Full optimisation of the synthetic sequence is described resulting in the synthesis of a simplified triamine core, lacking only the ester functionality required for (–)-martinellic acid and (+)-martinelline. Chapter 4 presents an asymmetric synthesis of (–)-martinellic acid and the first asymmetric synthesis of 4-epi-martinellic acid using the methodology developed in chapter 3, by incorporation of an ester functionality into substrate. Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in Chapters 2, 3 and 4.