Herein, the syntheses of nitrogen-containing heterocycles are applied to the areas of total synthesis and small molecule design for proteasome modulation. Indole alkaloids have been shown to display diverse biological activities. Moreover, it has been reported that the vast majority of biologically active compounds bare one or more nitrogen-containing heterocyclic moieties. Therefore, the synthesis of indole alkaloids baring nitrogen-containing heterocycles are of particular interest. Progress toward the first total synthesis of Tulongicin and its related natural product analogues is described. Particular emphasis is placed on the exploration and optimization of the key imidazoline cyclization and Friedel-Crafts alkylation steps. In addition, the design and synthesis of small molecule acyl Astemizole analogues containing various N-heterocyclic cores is discussed. These acyl Astemizole analogues were explored for their use in proteasome modulation and several active scaffolds were identified.
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