Stereoselective synthesis of novel non-aromatic nitrogen heterocycles

Heterocyclic chemistry is of crucial importance as a connection between organic and medicinal chemistry. In order to ensure an appropriate biological activity, many heterocycles have to be prepared in a stereodefined fashion. In our first approach we designed a three/four-step synthetic route whereby the pyridine can be converted into a collection of polyfunctionalized and structural diversified compounds, according to the diversity-oriented synthesis (DOS) concept. In particular, we took advantage of nitroso Diels-Alder (NDA) reaction to prepare stereoselectively arylnitroso derived Diels-Alder cycloadducts and nitrosocarbonyl derived Diels-Alder cycloadducts using 1,2-dihydropyridine as the diene component. The reductive cleavage of nitrosobenzene-derived cycloadducts allowed a novel and simple obtainment of substituted N-phenylpyrroles through the intermediacy of unconventional 2,7-diazabicyclo[2.2.1]heptenes. We also optimized the hetero-Cope rearrangement of acylnitroso derived cycloadducts to afford several 1,2,4-dioxazine derivatives. We developed three reductive elaborations of the newly synthesized dioxazines derivatives that ensured the regioselective preparation of piperidine-based scaffolds along with a novel of 4-oxa-1,3-diazabicyclo[3.3.1]nonene derivative. The second strategy represents the first aminocatalyzed acyl Mannich reaction involving N-acylquinolinium ions and dihydropyridinium ions via a synergistic catalysis. The methodology developed allows the unprecedented syntheses of carbamoyl dihydroquinoline and tetrahydropyridine derivatives with the introduction of chirality at the attacking carbon framework. We also proved the effectiveness of this process proposing a new enantioselective synthesis of the blockbuster drug Ritalin®.