Development of Lewis Acid Mediated Stereoselective Synthesis of Nitrogen Containing Heterocycles: Aza-Diels-Alder Reactions of 2H-Azirines and Cyclizations of Cationic Aminyl Radicals

This thesis deals with the development of synthetic methodologies for the preparation of enantioand diastereomerically enriched nitrogen-containing heterocycles. Asymmetric Lewis acid mediated Diels-Alder reactions with 2H-azirines as dienophiles have been studied. Diastereoselective reactions with enantiomerically pure auxiliary-derived 2H-azirines afforded substituted biand tri-cyclic azaheterocycles comprising a fused tetrahydropyridine–aziridine moiety in high yields and selectivities. It was found that the 8-phenylmenthol auxiliary was superior to Oppolzer’s bornane-2,10-sultam in these reactions. The influence of various Lewis acids on the reaction outcome was probed and their presence was crucial for successful reactions. The novel enantioselective aza-Diels-Alder reaction of benzyl2H-azirine-3-carboxylate was investigated with a range of chiral Lewis acids and provided the corresponding cycloadducts in moderate to low yields and selectivities. The 2H-azirines were synthesized from the corresponding acrylates via the vinyl azides. An improved and general procedure for thermolysis of vinyl azides into 2Hazirines was developed. Lewis acid mediated radical cyclizations of substituted N-chloro-4-pentenyland 4hexenylamines gave the corresponding pyrrolidines in high yields and in moderate to high diastereoselectivities. The reactivity and stereoselectivity were found to be strongly influenced by the substituents on the alkenylamine. On the other hand, no apparent correlation between the different Lewis acids applied and the obtained selectivities was observed. The relative stereochemistry of the cyclic products could be predicted using the Beckwith-Houk stereochemical model. The pyrrolidines were rearranged via aziridinium ions, which were ring-opened to the corresponding piperidines. The efforts to develop enantioselective radical cyclizations of cationic aminyl radicals proved unsuccessful. Reaction conditions and chiral Lewis acids were varied, yet, racemic product mixtures were obtained. The N-chloro-N-alkenylamines were synthesized in good yields.