| Resumo: | <p>Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly-found <em>para</em>-substituted benzene rings in drug design<sup>1</sup>. The utility of these cage structures derives from their superior pharmacokinetic properties compared to the parent aromatics, including improved solubility and reduced susceptibility to metabolism<sup>2,3</sup>. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesised by ring-opening of the inter-bridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions<sup>4</sup>. In contrast, scaffolds mimicking <em>meta</em>-substituted arenes are lacking due to the challenge of synthesising saturated isosteres that accurately reproduce substituent vectors<sup>5</sup>. Here we show that bicyclo[3.1.1]heptanes (BCHeps), hydrocarbons whose bridgehead substituents map precisely onto the geometry of <em>meta-</em>substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on 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 ADME properties of these analogues revealed enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this <em>meta-</em>arene analogue as an sp<sup>3</sup>-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a novel surrogate for <em>meta-</em>substituted benzene rings for implementation in drug discovery programmes.</p>
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