Stereoselective synthesis of constrained oxacyclic hydroxyethylene isosteres of aspartic protease inhibitors: aldol and Mukaiyama aldol methodologies for branched tetrahydrofuran 2-carboxylic acids

J Org Chem. 2005 Aug 19;70(17):6735-45. doi: 10.1021/jo050749y.

Abstract

The synthesis of diastereomeric 3-substituted-tetrahydrofuran 2-carboxylic acids in enantiopure form was achieved relying on aldol condensations of N-substituted alpha-amino aldehydes with enolates and enol silyl ethers of gamma-butyrolactone. Catalytic YbFOD leads to a high yield of a syn/syn-alpha-amino alcohol isomer. This was used as a constrained THF subunit in the synthesis of a peptidomimetic intended as an inhibitor of the enzyme BACE1, which is implicated in the cascade of events leading to plaque formation in Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / chemistry*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Carboxylic Acids / chemical synthesis*
  • Ethylenes / chemical synthesis*
  • Furans / chemical synthesis*
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Protease Inhibitors / chemical synthesis*
  • Spectrophotometry, Infrared

Substances

  • Aldehydes
  • Carboxylic Acids
  • Ethylenes
  • Furans
  • Protease Inhibitors
  • tetrahydrofuran
  • 3-hydroxybutanal
  • ethylene
  • Aspartic Acid Endopeptidases