Synthesis and functionalisation of a bifunctional normorphan 3D building block for medicinal chemistry

A multi-gram-scale synthetic route to a novel, bifunctional normorphan 3D building block bearing orthogonally reactive vinyl MIDA boronate and N-2,4-dimethoxybenzyl (DMB) amide functional handles has been developed. Synthetic manipulation at each of the functional handles has been demonstrated including Suzuki-Miyaura cross-coupling, exo-diastereoselective hydrogenation, N-DMB group removal and lactam reduction. Normorphan cores derived from the building block satisfied AstraZeneca's ‘rule of 2’ for building blocks and had a high fraction of sp3 hybridised carbon atoms (Fsp3). A virtual lead-like library of 344 compounds derived from the building block had attractive lead-like properties. The 3D building block has been commercialised by Redbrick Molecular and is currently available for purchase.