Research Projects

Phenyl rings are among the most prevalent structural motifs in pharmaceutical compounds, with nearly 45% of FDA-approved drugs featuring at least one phenyl group. Their widespread use stems from favorable electronic characteristics and synthetic accessibility. However, the overuse of phenyl groups can detrimentally affect key drug-like properties, such as aqueous solubility and metabolic stability. To address these challenges, medicinal chemists have increasingly turned to saturated, three-dimensional bicyclic scaffolds, such as bicyclo[1.1.1]pentanes (BCPs) and bicyclo[2.1.1]hexanes (BCHs), as bioisosteric replacements for phenyl rings. These rigid, saturated structures improve molecular complexity and fine-tune physicochemical attributes, thereby enhancing the pharmacokinetic and pharmacodynamic profiles of drug candidates and improving their chances of clinical success. Despite notable advancements, two major challenges remain: (1) the lack of general, asymmetric strategies for the remote incorporation of BCP motifs at aliphatic C(sp³)–H sites, and (2) the absence of methods for enantioselective functionalization at the C-2 bridgehead position of the BCP core.