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

Nicola Luise, Eleanor W. Wyatt, Gary Tarver, Paul Wyatt (Lead / Corresponding author)

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Abstract

An efficient hydrogenation protocol under continuous flow conditions was developed for the synthesis of underrepresented semi-saturated bicyclic fragments containing highly sp 3-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.

Original languageEnglish
Pages (from-to)1341-1349
Number of pages9
JournalEuropean Journal of Organic Chemistry
Volume2019
Issue number6
Early online date7 Jan 2019
DOIs
Publication statusPublished - 14 Feb 2019

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Keywords

  • Drug discovery
  • Flow reactions
  • Fused-ring systems
  • Heterocycles
  • Hydrogenation

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