Stereoselective synthesis of constrained azacyclic hydroxyethylene isosteres as aspartic protease inhibitors: dipolar cycloaddition and related methodologies toward branched pyrrolidine and pyrrolidinone carboxylic acids

J Org Chem. 2005 Aug 19;70(17):6746-56. doi: 10.1021/jo050740w.

Abstract

The synthesis of three vicinally substituted azacyclic carboxylic acids in enantiopure form was achieved from a common alpha-amino aldehyde originating from l-leucine. Pyrrolidines and pyrrolidinones were elaborated from alpha,beta-unsaturated gamma-hydroxy-delta-amino acids via azomethine ylide 1,3-dipolar addition and conjugate addition/cyclization strategies, respectively. The azacyclic amino acids were incorporated in a pseudopeptide now encompassing a hydroxyethylene isostere. Low nanomolar inhibition of BACE1, an enzyme implicated in the cascade of events leading to plaque formation in Alzheimer's disease, was found with a pyrrolidinone analogue.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Carboxylic Acids / chemistry*
  • Cyclization
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Protease Inhibitors / chemical synthesis*
  • Pyrrolidines / chemistry*
  • Pyrrolidinones / chemistry*
  • Spectrometry, Mass, Fast Atom Bombardment
  • Stereoisomerism

Substances

  • Carboxylic Acids
  • Protease Inhibitors
  • Pyrrolidines
  • Pyrrolidinones
  • Aspartic Acid Endopeptidases
  • pyrrolidine