Ladderanes: Stepping Up as Nonclassical ortho-Substituted Benzene Bioisosteres

Modulating the physicochemical properties of small-molecule active pharmaceutical ingredients (APIs) is a vital component of the drug discovery process. In recent years, investigations of the synthesis and application of saturated isosteres for aromatic rings have been growing and have often been shown to improve the properties of an API in matched pairs analysis. While saturated isosteres for para-substituted aromatic rings are well-established, replacing ortho-substituted rings, which comprise ∼12% of APIs, remains challenging. 1,2-Disubstituted cubane is a structurally ideal candidate, but its application is limited by a relatively lengthly synthesis. Here, we validate [2]-ladderane derivatives as simplified 1,2-disubstituted cubane analogs and bioisosteres of ortho-substituted benzene. We demonstrate the gram-scale synthesis of versatile building blocks and showcase their functionalization via medicinal chemistry-relevant transformations. By synthesizing and comparing matched pairs of bioactive compounds, we evaluate their physicochemical properties alongside their biochemical and cellular activities, establishing [2]-ladderanes as effective tools for medicinal chemistry.