Diamonds in Chemical Space: The Synthesis of Brexazine

Here we searched chemical space for small and novel diamond‐like, 3D‐shaped building blocks, which are very rare but highly valuable for medicinal chemistry because they can increase the natural product likeness of drug molecules and improve their selectivity, water solubility and metabolism. We explored the Generated DataBases (GDBs), which list all possible organic molecules up to a defined size, identified 162 norbornane containing ring systems related to the known trinorbornane, and took inspiration from its simpler substructure brexane to design brexazine as a new chiral and 3D‐shaped piperazine analog. The synthesis of brexazine was realized in 11 steps and 11.5% overall yield from a commercially available norbornene building block. These experiments illustrate the value of exploring chemical space from first principles to design new building blocks for drug discovery.