Research Projects

Replacing flat aromatic rings with bridged bicyclic structures has gained recognition as an effective strategy to improve the physicochemical and pharmacokinetic characteristics of drug candidates. Their inherent rigidity and metabolic stability are thought to provide distinctive biological effects, metabolic characteristics, and physicochemical properties. The recognition of these unique features has promoted intensified interest in developing and studying these bicycles. Due to their impressive ability to undergo cycloadditions with diverse substrates, bicyclo[1.1.0]butanes (BCBs) have become prominent tools for constructing three-dimensional bicyclic scaffolds. Heteroatom-substituted analogues of the saturated bicyclic scaffolds have been consistently found to provide enhanced water solubility, metabolic robustness, and diminished lipophilicity. Despite their potential, hetero-BCHeps have seen limited application in medicinal chemistry because of limited synthetic access. Therefore, developing new methods for synthesizing hetero-BCHeps, particularly with multiple heteroatoms is highly desirable. However, to date, nitrones remain the only reported coupling partners for the synthesis of N/O-bridged bicyclic structures with BCBs. Nonetheless, the continued search for novel and readily accessible coupling partners remains essential to advance the field. We have proposed to demonstrate that BCBs act as dipolarophiles toward reactive intermediates generated from oxaziridines, leading to a series of biologically interesting and structurally diverse bridged bicycles. Specifically, the nitrone intermediate generated in situ from oxaziridines will be employed in cycloaddition reactions with bicyclo[1.1.0]butanes (BCBs) to afford 1,2-N/O-bridged bicycles. By fine-tuning reaction conditions, we anticipate controlling the regioselectivity of the cycloaddition, enabling the selective formation of regioisomeric bridged bicycles through the use of carbonyl imine intermediates. Furthermore, the screening of reaction parameters is expected to facilitate the selective synthesis of 1,3-N/O-bridged bicycles, thus broadening the structural diversity and regioselectivity outcomes. Building on studies of BCB conversion to racemic and achiral products, further research will focus on the more challenging catalytic asymmetric transformations of BCBs by use of a chiral bidentate coordinating ligand in combination with a metal salt. N/O-bridged bicycles can serve as valuable synthetic intermediates by subsequent transformations such as reductive cleavage of the N–O bond or ring-opening processes. Such transformations will allow access to amino alcohol-functionalized cyclobutanes, which can be important scaffolds in medicinal chemistry and materials science. Additionally, this method can be applied to the synthesis of spirocyclic antiviral agents.