Total Synthesis of Caprazamycin A: Practical and Scalable Synthesis of syn-β-Hydroxyamino Acids and Introduction of a Fatty Acid Side Chain to 1,4-Diazepanone

J Am Chem Soc. 2019 May 29;141(21):8527-8540. doi: 10.1021/jacs.9b02220. Epub 2019 May 16.

Abstract

The first total synthesis of caprazamycin A (1), a representative liponucleoside antibiotic, is described. Diastereoselective aldol reactions of aldehydes 12 and 25-27, derived from uridine, with diethyl isocyanomalonate 13 and phenylcarbamate 21 were investigated using thiourea catalysts 14 or bases to synthesize syn-β-hydroxyamino acid derivatives. The 1,4-diazepanone core of 1 was constructed using a Mitsunobu reaction, and the fatty acid side chain was introduced using a stepwise sequence based on model studies. Notably, global deprotection was realized using palladium black and formic acid without hydrogenating the olefin in the uridine unit.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemical synthesis*
  • Amino Acids / chemistry
  • Azepines / chemical synthesis*
  • Azepines / chemistry*
  • Fatty Acids / chemistry*
  • Molecular Conformation
  • Stereoisomerism
  • Uridine / analogs & derivatives*
  • Uridine / chemical synthesis
  • Uridine / chemistry

Substances

  • 1,4-diazepane
  • Amino Acids
  • Azepines
  • Fatty Acids
  • caprazamycin A
  • Uridine