Practical and Facile Access to Bicyclo[3.1.1]heptanes: Potent Bioisosteres of meta-Substituted Benzenes

There is increasing interest in replacement of the planar aromatic rings of drug candidates with three-dimensional caged scaffolds in order to improve the physical properties, but bioisosteres of meta-substituted benzenes have remained elusive. We focused on the bicyclo[3.1.1]heptane (BCH) scaffold as a novel bioisostere of meta-substituted benzenes, anticipating that [3.1.1]propellane (2) would be a versatile precursor of diversely functionalized BCHs. Here, we describe a practical preparative method for [3.1.1]propellane from newly developed 1,5-diiodobicyclo[3.1.1]heptane (1), as well as difunctionalization reactions of 2 leading to functionalized BCHs. We also report postfunctionalization reactions of these products.

Automated summary

There is growing interest in replacing the planar aromatic rings in drug candidates with three-dimensional caged scaffolds. However, finding bioisosteres of meta-substituted benzenes has been a challenge. In this study, the bicyclo[3.1.1]heptane scaffold was explored as a novel bioisostere, and a practical method for its synthesis was developed.