Synthesis of 1,3-Disubstituted 3-Azabicyclo[3.2.0]heptane Libraries for Fragment-Based Drug Discovery

The 3-azabicyclo[3.2.0]heptane scaffold, yet underexplored in drug discovery, offers significant potential as a structural motif for medicinal chemistry. In this study, we present the synthesis of 1,3-disubstituted 3-azabicyclo[3.2.0]heptane derived building blocks via a 1,3-dipolar cycloaddition between the unique cyclobutene-1-sulfonyl fluoride (CBSF) building block and an azomethine ylide. To evaluate the chemical diversity and novelty of the fragments, we synthesized a covalent and a noncovalent fragment library inspired by an automated workflow. The synthesis and derivatization processes─including the formation of sulfonamides, carboxamides, ureas, and tertiary amines─are detailed, demonstrating the versatility and synthetic potential of 3-azabicyclo[3.2.0]heptane scaffolds in drug discovery.