Stereoselective crossed [2+2] cycloadditions as an entry to enantioenriched chiral bicyclo[2.1.1]hexanes and their investigation as trisubstituted benzene bioisosteres

• Applicant: Professor Dr. Johannes Walker
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 555018020

The proposed project aims to develop a powerful new stereoselective approach to polysubstituted bicyclo[2.1.1]hexane (BCH) compounds. These are in high demand in the pharmaceutical industry as scaffolds for benzene bioisosteres and as part of the "escape from flatland" hypothesis. The crossed [2+2] cycloaddition reaction is a versatile method of preparing these compounds, but stereoselective versions of this reaction are extremely rare. These are crucial for preparing substituted BCHs in high stereoselectivity, as required by medicinal chemistry. We will also apply our methods to prepare BCH-based isosteres of trisubstituted benzenes, and test them as first-in-class trisubstituted benzene bioisosteres. This project will contribute significantly not only to stereoselective synthesis, but also to biomedical research through the development of new benzene bioisosteres. The knowledge gained during this project will assist medicinal chemistry practitioners in making informed choices regarding bioisostere selection going forward.

• DFG Programme: Research Grants