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.

Citation

Toranosuke Iida, Junichiro Kanazawa, Tadafumi Matsunaga, Kazunori Miyamoto, Keiichi Hirano, Masanobu Uchiyama. Practical and Facile Access to Bicyclo[3.1.1]heptanes: Potent Bioisosteres of meta-Substituted Benzenes. Journal of the American Chemical Society. 2022 Dec 07;144(48):21848-21852

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PMID: 36342862

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