Stereoselective synthesis of uridine-derived nucleosyl amino acids

J Org Chem. 2011 Dec 16;76(24):10083-98. doi: 10.1021/jo201935w. Epub 2011 Nov 21.

Abstract

Novel hybrid structures of 5'-deoxyuridine and glycine were conceived and synthesized. Such nucleosyl amino acids (NAAs) represent simplified analogues of the core structure of muraymycin nucleoside antibiotics, making them useful synthetic building blocks for structure-activity relationship (SAR) studies. The key step of the developed synthetic route was the efficient and highly diastereoselective asymmetric hydrogenation of didehydro amino acid precursors toward protected NAAs. It was anticipated that the synthesis of unprotected muraymycin derivatives via this route would require a suitable intermediate protecting group at the N-3 of the uracil base. After initial attempts using PMB- and BOM-N-3 protection, both of which resulted in problematic deprotection steps, an N-3 protecting group-free route was envisaged. In spite of the pronounced acidity of the uracil-3-NH, this route worked equally efficient and with identical stereoselectivities as the initial strategies involving N-3 protection. The obtained NAA building blocks were employed for the synthesis of truncated 5'-deoxymuraymycin analogues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry*
  • Anti-Bacterial Agents / analysis
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology
  • Deoxyuridine / chemistry*
  • Humans
  • Hydrogenation
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Nucleotides / chemistry
  • Peptides / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship
  • Urea / chemistry

Substances

  • Amino Acids
  • Anti-Bacterial Agents
  • Nucleotides
  • Peptides
  • muraymycin A1
  • Urea
  • Deoxyuridine