A Scalable Synthesis of the Difluoromethyl-allo-threonyl Hydroxamate-Based LpxC Inhibitor LPC-058

J Org Chem. 2016 May 20;81(10):4393-8. doi: 10.1021/acs.joc.6b00589. Epub 2016 May 6.


The difluoromethyl-allo-threonyl hydroxamate-based compound LPC-058 is a potent inhibitor of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) in Gram-negative bacteria. A scalable synthesis of this compound is described. The key step in the synthetic sequence is a transition metal/base-catalyzed aldol reaction of methyl isocyanoacetate and difluoroacetone, giving rise to 4-(methoxycarbonyl)-5,5-disubstituted 2-oxazoline. A simple NMR-based determination of enantiomeric purity is also described.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology*
  • Benzamides / chemical synthesis*
  • Benzamides / pharmacology*
  • Catalysis
  • Gram-Negative Bacteria / drug effects
  • Gram-Negative Bacteria / enzymology
  • Indicators and Reagents
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation


  • Anti-Bacterial Agents
  • Benzamides
  • Indicators and Reagents
  • LPC-058
  • Amidohydrolases
  • UDP-3-O-acyl-N-acetylglucosamine deacetylase