Non-planar molecules can often be better drug candidates than “flat” ones. Replacing phenyl rings with “three-dimensional” units such as bicyclo[2.1.1]hexanes can be one option in this context. 1-Substituted bicyclo[2.1.1]hexan-2-ones (general structure pictured) can serve as useful intermediates in the synthesis of different 1,2-disubstituted bicyclo[2.1.1]hexane derivatives.

Woo-Jin Yoo, National Taiwan University, Taipei, and colleagues have developed a two-step transformation for the conversion of cyclobutanedione derivatives to 1-substituted bicyclo[2.1.1]hexan-2-ones. The team’s approach combines a transannular pinacol coupling reaction mediated by SmI₂ to form a vicinal diol with a bicyclo[2.1.1]hexane core, followed by an acid-catalyzed pinacol rearrangement using p-toluenesulfonic acid monohydrate to obtain the desired ketone. The starting diones can be prepared from commercially available 3-oxocyclobutane-1-carboxylic acid.

Using this procedure, the researchers obtained bicyclo[2.1.1]hexan-2-ones with a variety of substituents in the 1-position in mostly moderate to good yields. The products can serve as building blocks in drug development. The team demonstrated that they can be further transformed, e.g., into analogues of the antiparasitic and antiviral compound nitazoxanide. Overall, the work provides a useful synthetic path for the preparation of compounds with non-planar subunits that can be of interest in pharmaceutical chemistry.

• Synthesis of 1-Substituted Bicyclo[2.1.1]hexan-2-ones via a Sequential SmI₂-Mediated Pinacol Coupling and Acid-Catalyzed Pinacol Rearrangement Reaction,
  Yung-Chi Lee, Yi-Chen Chen, Chun-Fu Wu, Woo-Jin Yoo,
  Org. Lett. 2024.
  https://doi.org/10.1021/acs.orglett.4c03541