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

Abstract

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.

Fragment-to-Lead Medicinal Chemistry Publications in 2019

“…67,73 Synthesis of fragment libraries, in general, remains an area of intense research. In order to facilitate the synthesis of underrepresented fragment space, new reactions 74,75 and technologies are introduced, such as a continuous flow strategy 76 or an automated workflow that screens for reaction conditions to enable synthetic transformations and upscales synthesis in continuous flow. 77 Organic synthesis is still often a rate-limiting step in drug discovery, and its challenges and opportunities have been highlighted in a recent review.…”