In 2012, however, Stepan and colleagues showed that a replacement of the central phenyl ring in a γ-secretase inhibitor with the bicyclo [1.1.1]pentane improved its physicochemical properties and retained bioactivity (Scheme 1). Later, analogous replacements were undertaken with cubane and bicyclo[2.2.2]octane. 9 Therefore, during the past decade, these scaffolds proved to be useful in drug discovery, medicinal chemistry, and supramolecular chemistry. Recent studies, however, showed that all three bioisosteres had drawbacks. In bicyclo [1.1.1]pentane, the most popular among them today, the distance between two bridgehead carbon atoms (C-C) is 1.8 Å, which is ca. 35% shorter than that in the para-substituted phenyl ring (2.8 Å). Bicyclo[2.2.2]octane has a similar C-C distance (2.6 Å), but is much more lipophilic. Cubane, in turn, was recently shown to be unstable in the presence of transition metals, 15 mechanochemistry, or heating. In this work, we have rationally designed, synthesized, and characterized the ideal bioisoster of the para-substituted phenyl ring -2-oxabicyclo[2.2.2]octane (Figure ). Design. In the design of the ideal phenyl bioisoster, we first needed to keep the advantages of the previously used cores: their conformational rigidity, metabolic stability, nonchirality, and collinearity of vectors ( = 180º). At the same time, we needed to address their drawbacks: C-C distance, and lipophilicity. After thinking for a while (please, see SI for the details of the design), we decided to stick to the stable bicyclo[2.2.2]octane structure, because of its appropriate C-C distance, and decorate it with an oxygen atom. In particular, replacing one carbon atom with oxygen 23 would give 2-oxabicyclo[2.2.2]octane with similar geometry and reduced lipophilicity (Figure ). Also, this structure should be chemically stable because it is a simple derivative of tetrahydropyran. 24