Total synthesis and biological evaluation of pacidamycin D and its 3'-hydroxy analogue

J Org Chem. 2012 Feb 3;77(3):1367-77. doi: 10.1021/jo202159q. Epub 2012 Jan 18.

Abstract

Full details of the total synthesis of pacidamycin D (4) and its 3'-hydroxy analogue 32 are described. The chemically labile Z-oxyacyl enamide moiety is the most challenging chemical structure found in uridylpeptide natural products. Key elements of our approach to the synthesis of 4 include the efficient and stereocontrolled construction of the Z-oxyvinyl halides 6 and 7 and their copper-catalyzed cross-coupling with the tetrapeptide carboxamide 5, a thermally unstable compound containing a number of potentially reactive functional groups. This synthetic route also allowed us to easily prepare 3'-hydroxy analogue 32. The assemblage by cross-coupling of the Z-oxyvinyl halide 6 and the carboxamide 5 at a late stage of the synthesis provided ready access to a range of uridylpeptide antibiotics and their analogues, despite their inherent labile nature with potential epimerization, simply by altering the tetrapeptide moiety.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Catalysis
  • Chemistry Techniques, Synthetic / methods*
  • Copper / chemistry
  • Microbial Sensitivity Tests
  • Peptides / chemical synthesis*
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Pseudomonas aeruginosa / drug effects
  • Pyrimidine Nucleosides / chemical synthesis*
  • Pyrimidine Nucleosides / chemistry
  • Pyrimidine Nucleosides / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Peptides
  • Pyrimidine Nucleosides
  • pacidamycin D
  • Copper