Synthesis of (-)-PNU-286607 by asymmetric cyclization of alkylidene barbiturates

J Am Chem Soc. 2009 Mar 25;131(11):3991-7. doi: 10.1021/ja808014h.

Abstract

PNU-286607 is the first member of a promising, novel class of antibacterial agents that act by inhibiting bacterial DNA gyrase, a target of clinical significance. Importantly, PNU-286607 displays little cross-resistance with marketed antibacterial agents and is active against methicillin-resistant staphylococcus aureus (MRSA) and fluoroquinoline-resistant bacterial strains. Despite the apparent stereochemical complexity of this unique spirocyclic barbituric acid compound, the racemic core is accessible by a two-step route employing a relatively obscure rearrangement of vinyl anilines, known in the literature as the "tert-amino effect." After a full investigation of the stereochemical course of the racemic reaction, starting with the meso cis-dimethylmorpholine, a practical asymmetric variant of this process was developed.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / antagonists & inhibitors
  • Barbiturates / chemistry*
  • Barbiturates / pharmacology*
  • Cyclization
  • Drug Resistance, Bacterial
  • Fluoroquinolones
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Spiro Compounds / chemical synthesis*
  • Stereoisomerism
  • Topoisomerase II Inhibitors

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Barbiturates
  • Fluoroquinolones
  • Heterocyclic Compounds, 4 or More Rings
  • PNU-286607
  • Spiro Compounds
  • Topoisomerase II Inhibitors