title: A Scalable Synthesis of the Difluoromethyl-allo-threonyl Hydroxamate-Based LpxC Inhibitor LPC-058.
abstract: 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.
authors.affiliation: Department of Chemistry, Duke University , Durham, North Carolina 27708, United States.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Chemistry, Duke University , Durham, North Carolina 27708, United States.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Gopalaswamy
authors.affiliation: Department of Chemistry, Duke University , Durham, North Carolina 27708, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Navas
authors.affiliation: Department of Chemistry, Duke University , Durham, North Carolina 27708, United States.|Department of Biochemistry, Duke University Medical Center , Durham, North Carolina 27710, United States.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Toone
authors.affiliation: Department of Chemistry, Duke University , Durham, North Carolina 27708, United States.|Department of Biochemistry, Duke University Medical Center , Durham, North Carolina 27710, United States.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhou
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D002384:Catalysis; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000201:enzymology; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation
chemical_list: D000900:Anti-Bacterial Agents; D001549:Benzamides; D007202:Indicators and Reagents; C000627229:LPC-058; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase