Organic Chemistry

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



Small-ring cage hydrocarbons are common bioisosteres for para-substituted benzene rings in drug design, exhibiting superior pharmacokinetic properties compared to the parent aromatics. In contrast, scaffolds mimicking meta-substituted arenes are lacking due to the challenge of synthesising saturated isosteres that accurately reproduce the substituent vectors of the corresponding arene. Here we report the use of [3.1.1]propellane as a convenient and scalable precursor to bicyclo[3.1.1]heptanes (BCHeps), hydrocarbons whose bridgehead substituents map precisely onto the geometry of meta-substituted benzenes. This precursor undergoes a range of radical-based transformations to generate medicinally-relevant carbon- and heteroatom-substituted BCHeps, including BCHep pharmaceutical analogues. Comparison of ADME properties of the latter reveals improved metabolic stability relative to their parent drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design.


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Supplementary material

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Supplementary Information
Experimental procedures, characterisation data, x-ray crystallography details, computational details, ADME / physicochemical property details, copies of 1H and 13C NMR spectra
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Coordinates file
Coordinates for computational structures
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Cif file
Cif file for crystalline BCHep compounds