Abstract: this proposal is aimed at the investigation of a novel route for the synthesis of benzoazetidines, which are four-membered nitrogen heterocycles fused with an aromatic ring. About 59% of the top selling drugs contain a nitrogen heterocycle, to witness the importance of these structures in active pharmaceutical ingredients. Despite azetidones (2-oxo azetidines) are the most common heterocyles found in antibiotics, no drug bearing a simple azetidine or benzoazetidines moiety has made on the market yet. This is mostly due with the difficulties associated with the synthesis of azetidines. The known preparations proceed in low yield, employ transition metals and hash reaction conditions. There are only few syntheses known which are far from optimal. We found serendipitously that benzoazetidines can be prepared in very mild conditions without the usage of transition metals (via organocatalysis), although the reaction requires a thorough optimization to be synthetically useful. The purpose of this proposal is to find a set of optimal condition, (WP1) to investigate the scope of this novel reaction (WP2), to possibly develop an asymmetric version (WP3) and finally to initiate a collaboration with a private or public partner in order to test these highly interesting and promising new compounds.
This research is aimed at the synthesis of benzoazetidines. While nitrogen-containing heterocycles are present in a number of pharmaceutically active substances, there are only few synthesis of these structures. Those preparations are low yielding and often requires hash conditions or the usage of transition metals. An easy preparation of these molecules can boost the research in this area, opening new horizon in the field of medicinal chemistry. Our proposed synthesis, once optimized, can access benzoazetidines in just three synthetic steps, and there is even the possibility to develop a one-pot, cascade reaction. This proposal, if successful can offer a set of new tools for the preparation of novel drugs, in order to target e.g. neglected disease. Furthermore, the mild reaction conditions, which respect the principles of green chemistry, could be exploited for the development of large-scale, environmentally benign synthesis.