PhotoazaBCP · Photochemical Strategies for the Synthesis of 2-azaBCPs as Novel Bioisosteres in Drug Discovery

This proposal tackles one of the key frontiers in modern medicinal chemistry: how to replace flat aromatic rings with three-dimensional, nitrogen-containing bioisosteres that improve solubility, stability, and drug-like properties. The project introduces a new photochemical platform that combines nitrene chemistry with strained bicyclo[1.1.0]butanes (BCBs) to access 2-azabicyclo[1.1.1]pentanes (2-azaBCPs), an unprecedented class of building blocks. By exploiting visible-light activation modes, the strategy will enable controlled nitrene generation and selective reactivity with BCBs under mild conditions. Alongside its synthetic applications, the project will also generate fundamental new knowledge in nitrene photochemistry, an area with remarkable yet underexplored potential. The project includes the development of modular photoredox diversification via carboxylates, and metallaphotoredox couplings for the incorporation of 2-azaBCPs into complex molecules. If successful, this approach will deliver a general entry into nitrogen-rich scaffolds that act as bioisosteres of both aromatic heterocycles and saturated amines, redefining what is possible in bioisosteric replacement. For Prof. Ruffoni, the fellowship will establish him as a leader in photochemistry and catalysis in Europe, accelerating group growth and supporting pioneering research programs. For the applicant, it provides advanced training, independence, and international visibility to build a competitive profile in Europe. More broadly, the work promotes green chemistry through visible-light synthesis, expands chemical space for medicinal chemistry, and enables bioisosteric analogues of drugs such as Losmapimod and Siponimod, underscoring its pharmaceutical relevance. Altogether, the project places European chemistry at the forefront of bioisosteric replacement, benefiting academia, healthcare, and society.