Synthesis of meta-Substituted Arene Bioisosteres from [3.1.1]Propellane
Edward Anderson describes the synthesis of meta-substituted arene from [3.1.1]propellane via a BCHep.
Bicyclo[1.1.1]pentanes (BCPs) have emerged as important structures in drug development as bioisosteres for para-substituted benzene rings. The group of Professor Edward Anderson at the University of Oxford (UK) has had a long-standing interest in the molecule [1.1.1]propellane, the usual precursor to a BCP, from both synthetic and mechanistic perspectives. Professor Anderson mentioned that “BCPs display increased solubility and metabolic stability compared to their aromatic parents, while retaining the 180° substitution geometry and, often, bioactivity.” He added that “BCPs have spearheaded an armada of small-ring cage hydrocarbons that ‘escape the aromatic flatland’ through their three-dimensionality, which has been linked to higher clinical success rates of drug candidates. However, a bioisostere for meta-substituted arenes that accurately mimics their 120° substitution geometry has to date been absent from this collection.” Therefore, it was obvious to extend his group’s research into ring-opening reactions of [1.1.1]propellane in order to explore its next stable higher congener, namely [3.1.1]propellane.
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