A Versatile Approach to CF3 -Containing 2-Pyrrolidones by Tandem Michael Addition-Cyclization: Exemplification in the Synthesis of Amidine Class BACE1 Inhibitors

Chemistry. 2015 Aug 10;21(33):11719-26. doi: 10.1002/chem.201501662. Epub 2015 Jul 3.

Abstract

The synthesis of new fluorinated pyrrolidones starting from unprotected amino esters and amino nitriles through a Michael addition-lactamization sequence is described. The resulting CF3 -containing building blocks, bearing a quaternary stereogenic center adjacent to the fluorinated group, have been converted into amino pyrrolidines that display potent β-secretase 1 (BACE1) inhibitory activity. This work constitutes an example of selective fluorination as a valid strategy for the modulation of physicochemical and biological properties of lead compounds in drug discovery.

Keywords: cyclization; drug discovery; enzymes; fluorine; inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidines / chemical synthesis*
  • Amidines / pharmacology*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / chemistry*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry*
  • Cyclization
  • Drug Discovery
  • Hydrocarbons, Fluorinated / chemistry*
  • Hydrocarbons, Fluorinated / pharmacology*
  • Molecular Structure
  • Pyrrolidinones / chemistry*
  • Pyrrolidinones / pharmacology*
  • Stereoisomerism

Substances

  • Amidines
  • Hydrocarbons, Fluorinated
  • Pyrrolidinones
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • 2-pyrrolidone