A Versatile Boc Solid Phase Synthesis of Daptomycin and Analogues Using Site Specific, On-Resin Ozonolysis to Install the Kynurenine Residue

Chemistry. 2019 Nov 7;25(62):14101-14107. doi: 10.1002/chem.201903725. Epub 2019 Sep 30.

Abstract

A de novo solid-phase synthesis of the cyclic lipodepsipeptide daptomycin via Boc chemistry was achieved. The challenging ester bond formation between the nonproteinogenic amino acid kynurenine was achieved by esterification of a threonine residue with a protected tryptophan. Subsequent late-stage on-resin ozonolysis, inspired by the biomimetic pathway, afforded the kynurenine residue directly. Synthetic daptomycin possessed potent antimicrobial activity (MIC100 =1.0 μg mL-1 ) against S. aureus, while five other daptomycin analogues containing (2R,3R)-3-methylglutamic acid, (2S,4S)-4-methylglutamic acid or canonical glutamic acid at position twelve prepared using this new methodology were all inactive, clearly establishing that the (2S,3R)-3-methylglutamic acid plays a key role in the antimicrobial activity of daptomycin.

Keywords: Boc chemistry; cyclic lipodepsipeptides; daptomycin; on-resin ozonolysis; solid-phase synthesis.

MeSH terms

  • Anti-Infective Agents / chemical synthesis*
  • Anti-Infective Agents / chemistry
  • Daptomycin / analogs & derivatives
  • Daptomycin / chemical synthesis*
  • Drug Evaluation, Preclinical
  • Glutamates / chemistry
  • Glutamic Acid / analogs & derivatives
  • Glutamic Acid / chemistry
  • Kynurenine / chemistry*
  • Ozone / chemistry*
  • Solid-Phase Synthesis Techniques
  • Staphylococcus aureus / drug effects
  • Threonine / chemistry

Substances

  • 3-methylglutamic acid
  • Anti-Infective Agents
  • Glutamates
  • 4-methylglutamic acid
  • Threonine
  • Kynurenine
  • Glutamic Acid
  • Ozone
  • Daptomycin