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

• Published in: Nature (London) 2022-11, Vol.611 (7937), p.721-726
• Main Authors: Frank, Nils, Nugent, Jeremy, Shire, Bethany R., Pickford, Helena D., Rabe, Patrick, Sterling, Alistair J., Zarganes-Tzitzikas, Tryfon, Grimes, Thomas, Thompson, Amber L., Smith, Russell C., Schofield, Christopher J., Brennan, Paul E., Duarte, Fernanda, Anderson, Edward A.
• Format: Article
• Language: English
• Subjects: 119/118; 140/131; 639/638/309/2144; 639/638/403/933; Aromatic compounds; Benzene; Cages; Chemistry; Drug development; Heptanes; Humanities and Social Sciences; Hydrocarbons; Metabolism; multidisciplinary; Pentane; Pharmacokinetics; Ring opening; Science; Science (multidisciplinary); Solubility; Substitutes; Synthesis
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-05290-z

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. The potential power of the saturated carbocycle bicyclo[3.1.1]heptane as a beneficial motif for improving the pharmacokinetic and physicochemical properties of drug candidates is demonstrated.