Diastereoselective Synthesis of Highly Substituted, Amino- and Pyrrolidino-Tetrahydrofurans as Lead-Like Molecular Scaffolds

Steven M. Wales, Elena G. Merisor, Holly V. Adcock, Christopher A. Pearce, Ian R. Strutt, William Lewis, Daniel Hamza, Christopher J. Moody*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

4 Citations (Scopus)

Abstract

A series of highly substituted tetrahydrofurans (THFs), decorated with modifiable 2-aryl, 3-carboxy and 4-amino substituents, has been prepared for biological evaluation within the European Lead Factory. Diastereoselective reductive amination of pre-functionalised 4-oxofurans, readily prepared from cinnamate esters via oxa-Michael/Dieckmann annulation, provided the requisite THF cores on gram scale with three contiguous stereocentres, including full substitution at C-3. In a second series, a pyrrolidine ring was fused to the same oxofuran scaffold via an intramolecular reductive amination, inverting the configuration at C-4 relative to the other ring substituents. The resulting compounds, which displayed desirable physical properties as lead-like scaffolds, were derivatised into a small library of 24 compounds, demonstrating their ability to serve as starting points for drug discovery. Ultimately, this chemistry enabled the preparation of 1948 THF-containing compounds for inclusion in the Joint European Compound Library.

Original languageEnglish
Pages (from-to)8233-8239
Number of pages7
JournalChemistry - A European Journal
Volume24
Issue number32
Early online date14 Apr 2018
DOIs
Publication statusPublished - 7 Jun 2018

Keywords

  • drug discovery
  • heterocycles
  • lead-oriented synthesis
  • pyrrolidines
  • tetrahydrofurans

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