Research Projects

This project aims to develop innovative, eco-friendly synthetic methods for constructing enantioenriched (chiral) heterocyclic compounds, which are essential in drug discovery due to their influence on pharmacological and physicochemical properties. We seek to access these complex molecules through simple, metal-free, and atom-economical organocatalytic strategies. Our approach combines two key reactions: an asymmetric Aza-Mannich addition, where the amine group of a 1,3-amphoteric N-substituted oxetan-3-amine adds to a cyclic N-sulfimine to generate the first stereocenter; and a ring-opening desymmetrization, in which the strained oxetane ring is cleaved to form a second chiral center and establish the core imidazolidine structure. This method exploits the unique amphoteric nature of N-substituted oxetan-3-amines, which contain both nucleophilic and electrophilic sites. These molecules react with polarized π-systems (such as imines) in the presence of bifunctional organocatalysts—specifically squaramide- or thiourea-based cinchona derivatives—that activate both components and enable highly enantioselective [3 + 2] annulations. The resulting chiral polyheterocycles—imidazolidines, imidazo-azetidines, pyrrolo-diazananes, and imidazo-diazananes—occupy underexplored chemical space and offer valuable frameworks for medicinal chemistry. These scaffolds contain multiple stereocenters and can be further diversified for biological screening. To broaden the scope, we also plan to design new amphoteric systems, such as 1,4- and 1,5-substituted oxetane-amines, enabling ring expansion into diazanane and diazepane derivatives. Additionally, we will develop oxetan-3-amines derived from amino acids and peptides to create chiral peptidomimetics and macrocycles. A further extension of this work involves transforming FDA-approved amine drugs into novel enantioenriched tetracyclic analogs, which will be evaluated for biological activity. This strategy allows for the repurposing of existing drugs and may lead to the discovery of first-in-class therapeutic agents. Overall, our work introduces a versatile, sustainable, and pharmaceutically relevant approach for synthesizing complex, chiral heterocycles.