Modular Assembly of Bioisosteric Bridged Aza-frameworks via Strained Ring Release

Recent advancements in synthetic chemistry have sparked significant interest in bridged compounds, particularly azabicyclo[x,1,1]alkanes (ABCAs), which have emerged as critical structural motifs in medicinal chemistry. These compounds are highly valued for their unique geometric constraints, enhanced target selectivity, and favorable pharmacokinetic profiles, making them valuable tools in drug discovery. However, despite their importance, the construction of diverse ABCA motifs remains a significant challenge, as existing methodologies are often limited to specific ring systems and substituents. In this study, we present a modular synthetic strategy for the construction of ABCA motifs. The key of this approach lies in the successful synthesis of a series of highly strained azatricycloalkanes, such as 1-azatricyclo[4.1.0.0²,⁷]heptane. By leveraging stereocontrolled transformations of the strained C–N bonds within these azatricycloalkanes, we have synthesized a wide range of ABCA derivatives with unprecedented structural diversity. This methodology has been effectively utilized in the development of novel orexin receptor antagonists and bioisosteres, showcasing its potential to advance drug discovery for therapeutic applications.