Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane

Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design(1). The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism(2,3). A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions(4). By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors(5). Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp(3)-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.

Automated summary

Small-ring cage hydrocarbons are popular bioisosteres for para-substituted benzene rings in drug design. In this study, we synthesized hydrocarbons called bicyclo[3.1.1]heptanes (BCHeps) from [3.1.1]propellane, which have geometric correspondence to meta-substituted benzenes. The BCHeps can be easily transformed into medicinally relevant carbon- and heteroatom-substituted compounds, displaying enhanced metabolic stability compared to their parent arene-containing drugs. This research demonstrates the potential of BCHeps as sp(3)-rich motifs in drug design and provides a new surrogate for meta-substituted benzene rings in drug discovery programs.