Scaffold hopping vanuit geprivilegieerde diazepine-derivaten naar nieuwe tricyclische motieven

While the benzodiazepine drug class has been amongst the most prescribed medication globally since its discovery in the 1950s, the search for structurally related biologically active compounds is of major relevance to the pharmaceutical industry. In previous work in our group, we made the serendipitous finding that diazepinedione systems can undergo a rearrangement reaction, giving rise to completely new molecules with potentially interesting biological activities. These biological activities include antitumor, antimalarial, antibacterial, and central nervous system activities. In the latter case, the compounds could potentially be used in the treatment of anxiety and sleep disorders, and for the enhancement of memory. Owing to their evidently privileged topology, we have aimed to contribute to the synthetic repertoire for the preparation of both this particular class of promising scaffolds, and closely related scaffolds. Two different approaches have been developed for the preparation of these tricyclic motifs. In a first approach, annulated diazepinedione precursors were subjected to optimized rearrangement conditions to yield their corresponding tricyclic derivatives. In a second approach, tricyclic motifs were constructed by assembling the pivot heterocycle in a (3+3) cyclocondensation fashion. The key synthetic steps in the latter approach are: (1) the construction of a challenging amide linker connecting the two peripheral heterocycles; and (2) a palladium-catalyzed intramolecular C-H arylation event to form the key heterocycle. Both approaches make use of readily available starting materials. Throughout the synthetic explorations in this dissertation, continuous flow chemistry was adopted as enabling laboratory technique, and several flow protocols were developed with a much wider applicability than just our target molecules. This includes an efficient reaction protocol for the conversion of benzodiazepine materials into promising tricyclic derivatives, as well as a fast and efficient protocol for the formation of amides from low nucleophilic amines and esters. The final result was a successful preparation of the [1,3]oxazolo[4,5-c]-quinolin-4(5H)-one scaffold and the four isomeric [1,3]oxazolo[4,5-c]-1-naphthyridin-4(5H)-one scaffolds, in all cases allowing for the introduction of relevant points of diversity into the tricyclic products.status: publishe