A new synthetic approach to biaryls of the rhazinilam type. Application to synthesis of three novel phenylpyridine-carbamate analogues

Org Biomol Chem. 2007 Jan 7;5(1):175-83. doi: 10.1039/b613173e. Epub 2006 Nov 23.

Abstract

The synthesis of three novel racemic phenylpyridine-carbamate analogues of rhazinilam and their biological evaluation as inhibitors of microtubule assembly and disassembly by interaction with tubulin are described. The sterically hindered ortho-disubstituted biaryl unit as the challenging key structural element is first obtained by a sequential regiocontrolled nucleophilic addition of a lithium ortho-lithiohomobenzylic alkoxide species to 3-bromo-5-oxazolyl pyridine as the electrophile and a subsequent oxidation step. The incorporation of the amino group by replacement of the bromide has been achieved using a Buchwald-Hartwig amination coupling. Ultimate deprotection steps furnished free-amino and free-hydroxyl appendages which were connected by phosgenation to furnish the nine-membered median carbamate ring.

MeSH terms

  • Alkaloids / chemistry*
  • Alkaloids / classification
  • Alkaloids / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Indolizines / chemistry
  • Indolizines / classification
  • Indolizines / therapeutic use
  • Inhibitory Concentration 50
  • Lactams / chemistry
  • Lactams / classification
  • Lactams / therapeutic use
  • Molecular Structure
  • Phenylcarbamates / chemical synthesis*
  • Phenylcarbamates / chemistry*
  • Phenylcarbamates / metabolism
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry*
  • Pyridines / metabolism
  • Tubulin / drug effects*

Substances

  • Alkaloids
  • Indolizines
  • Lactams
  • Phenylcarbamates
  • Pyridines
  • Tubulin
  • rhazinilam