Research Projects

Nitrogen-based heterocycles represent 60% of small-molecule-approved drugs. Increasing demand for sp3-rich novel N-heterocyclic scaffolds as a bioisosteric replacement in drug discovery platforms has continued to drive the development of novel methods for the synthesis of these important molecules. Among various sp3-rich N-heterocycles, azetidine has emerged as a valuable class of strained saturated azacycles, garnering the interest of organic and medicinal chemists as a bioisosteres of pyrrolidine and piperidine, two most important N-heterocycles prevalent in marketed drugs. Also, the bioisosteric replacement of the azetidine ring into pharmaceutically relevant frameworks can enhance pharmacokinetic features. These advances have led to the development of several marketed drugs that contain an azetidine ring. Also, it motivates the organic chemist to develop effective methodologies for the construction of the functionalized azetidine ring. The strain-release-driven ring opening of the azabicyclo[1.1.0]butane (ABB) has emerged as a novel synthetic route to access diverse azetidines. Over the years, several methods were developed for the ring opening of the ABB ring using various nucleophiles. However, most of these current methods installed functional groups at the C3-position, and a small subset of N-functionalization has been achieved to date. More importantly, the catalytic and enantioselective N-activation of ABB ring with a suitable electrophile remains unknown. Considering the importance of chirality in determining the biological activity of drug molecules, several catalytic and asymmetric synthetic strategies for the strain release-driven ring opening of bicyclo[1.1.0]butane (BCB) ring have been developed over the last three years, However, catalytic & asymmetric synthesis of divergent aztidines scaffolds via strain release-driven ring opening of azabicy-clo[1.1.0]butane (ABB) ring remains unknown despite the presence of chiral azetidines with C3-quaternary carbon in a good number of bioactive molecules. We, therefore, would like to address this synthetic gap and pursue the development of catalytic & asymmetric ring opening of ABB ring. We hypothesized that the nitrogen lone pair of ABB ring would be available for electrophilic activation in the presence of appropriate electrophile and transition metal complex. The asymmetric allylic amination using ABB-boronate complex, generated from the corresponding ABB-Li and boronic ester, followed by 1,2-metallate rearrangement to neutralize the positive charge on the N-atom. Similarly, Pd or Ir-catalyzed asymmetric allylic amination of ABB-carbinols ring engages the cleavage of the strained ABB central bond through a spirocyclization to neutralize the positive charge on the nitrogen atom to give spiro-epoxy N-allylated azetidines, an important scaffold for future drug discovery studies.We hypothesized that the nitrogen lone pair of the ABB ring would be available as a nucleophile for the Lewis acid or copper-catalyzed ring opening of D-A cyclopropane as well. Further, manipulation of C-B bond to C-O, C-N, and C-C bonds will allow access to diversely functionalized azetidines. We are also interested in developing asymmetric multicomponent reactions using ABB for the synthesis of chiral compounds. Finally, we would like to check the bioactivity of our synthesized compounds in the fly lab of Dr. Das from the Department of Bioscience and Biotechnology, IIT Kharagpur. Based on the early literature on the antidepressant activity of azetidine compounds, we would like to study the antidepressant property of our synthesized compounds using the Drosophila depression model induced by social isolation, which remains mostly unexplored till today. Also, we would like to explore the antimicrobial activity of our synthesized compounds as well.