Total syntheses and anticholinesterase activities of (3aS)-N(8)-norphysostigmine, (3aS)-N(8)-norphenserine, their antipodal isomers, and other N(8)-substituted analogues

J Med Chem. 1997 Aug 29;40(18):2895-901. doi: 10.1021/jm970210v.

Abstract

N(8)-Benzylesermethole (6) was prepared from 5-methoxytryptamine (1) in five steps. Resolution of compound 6 by dibenzoyl- and ditoluyltartaric acid provided enantiomers (-)- and (+)-7. After demethylation, reaction with isocyanates and catalytic debenzylation over hydrogen, the total syntheses of (-)- and (+)-N(8)-norphysostigmine [(-)- and (+)-11] and (-)- and (+)-N(8)-norphenserine [(-)- and (+)-12] were accomplished, (-)-N(8)-Norphysostigmine [(-)-11] and (-)-N(8)-norphenserine [(-)-12] were also obtained by transformations of natural physostigmine [(-)-13] and phenserine [(-)-14] prepared from (-)-13. The absolute configurations and optical purity of compounds (-)-11, (-)-12, (+)-11, and (+)-12 were confirmed by a comparison of their optical rotations with those of the compounds synthesized from physostigmine [(-)-13]. The anticholinesterase activities of N(8)-nor- and N(8)-substituted analogues, (-)- and (+)-9, -10, -11, -12, 15, and 16, were compared with those of physostigmine [(-)- and (+)-13] and phenserine [(-)- and (+)-14] and are reported.

MeSH terms

  • Acetylcholinesterase / blood*
  • Acetylcholinesterase / isolation & purification
  • Butyrylcholinesterase / blood*
  • Butyrylcholinesterase / isolation & purification
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Erythrocytes / enzymology
  • Humans
  • Indicators and Reagents
  • Isomerism
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Physostigmine / analogs & derivatives*
  • Physostigmine / chemical synthesis
  • Physostigmine / chemistry
  • Physostigmine / pharmacology
  • Structure-Activity Relationship

Substances

  • Cholinesterase Inhibitors
  • Indicators and Reagents
  • N(8)-norphenserine
  • N(8)-norphysostigmine
  • Physostigmine
  • Acetylcholinesterase
  • Butyrylcholinesterase