In pharmaceutical chemistry, using less “flat” alternatives to arene groups can lead to improved drug properties. Bicyclo[3.1.1]heptanes, for example, can replace meta-substituted arenes while retaining a very similar overall structure. Heteroatoms in such groups can improve the solubility and efficacy of the resulting drug candidates. However, the synthesis of hetero-atom-containing variants of bicyclo[3.1.1]heptanes could use further exploration and new approaches.

Frank Glorius, University of Münster, Germany, and colleagues have developed a light-promoted method for the cyclization of bicyclo[1.1.0]butanes that leads to two different types of products, dependent on the solvent mixture: either oxygen-containing bicyclo[3.1.1]heptanes (general structure pictured above on the left) or highly functionalized cyclobutanes ((general structure pictured above on the right). The team used an iridium-based photocatalyst (PC) together with Na₂CO₃ as a base and performed the reactions under blue LED light.

Subtle changes in the solvent ratios lead to different reaction pathways. When the researchers used a 1:1 mixture of MeCN and CH₂Cl₂, they obtained the oxa-bicyclic heptane products via a 1,3-cyclization. When they used CH₂Cl₂ with five equivalents of MeCN instead, a highly diastereoselective 1,2-cyclization gave multi-functionalized cyclobutanes. The team explains these divergent cyclizations by a favored, rapid conversion of the bicyclo[1.1.0]butane to a cyclobutene intermediate in the second solvent system. Overall, the developed approach provides access to a broad array of products from bicyclo[1.1.0]butanes.

• Solvent‐Dependent Divergent Cyclization of Bicyclo[1.1.0]butanes,
  Fuhao Zhang, Subhabrata Dutta, Alessia Petti, Debanjan Rana, Constantin G. Daniliuc, Frank Glorius,
  Angew. Chem. Int. Ed. 2024.
  https://doi.org/10.1002/anie.202418239