A Continuous Flow Strategy for the Facile Synthesis and Elaboration of Semi‐Saturated Heterobicyclic Fragments

An efficient hydrogenation protocol under continuous flow conditions was developed for the synthesis of underrepresented semi‐saturated bicyclic fragments containing highly sp3‐rich skeletons for fragment‐based drug discovery (FBDD) programs. Excellent yields were generally achieved by using Pd/C (10 % w/w) and RaNi at 25–150 °C under 4–100 bar of hydrogen pressure. The generated fragments, with appropriate physicochemical properties, present diverse hydrogen‐bonding pharmacophores and useful vectors for their synthetic elaboration in the optimization stage. Successive, simple functionalizations in continuous flow were accomplished to demonstrate the opportunity to develop multi‐step continuous flow synthesis of valuable starting points for FBDD campaigns. A conclusive quality control (QC) was essential to discard those structures which do not fit the typical fragment library parameters. Hydrogenation under continuous flow conditions was employed to deliver semi‐saturated fragments, presenting ideal physicochemical properties and characterized by key motifs for both their synthetic elaboration and binding to biological targets. Their facile functionalization, in continuous flow, represents a valid opportunity for the multi‐step synthesis of functionalized sp3‐rich fragments.