1,2-Difunctionalized bicyclo[1.1.1]pentanes: Long–sought-after mimetics for ortho/meta-substituted arenes

Abstract

Significance Bioisoteric replacements for aromatic rings to improve medicinal properties are in high demand. This work presents a comprehensive analysis of heretofore-inaccessible 1,2-difunctionalized bicyclo[1.1.1]pentanes from both chemical and biological vantage points. This analysis will aid those in drug discovery regarding when the application of such systems makes sense and how to access them in such circumstances. The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.