Synthesis of PDE IVb Inhibitors. 3. Synthesis of (+)-, (-)-, and (±)-7-[3-(cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one via reductive domino transformations of 3-β-carbomethoxyethyl-substituted six-membered cyclic nitronates

J Org Chem. 2012 Jun 15;77(12):5465-9. doi: 10.1021/jo300955n. Epub 2012 Jun 6.

Abstract

Simple three-step asymmetric and racemic syntheses of GlaxoSmithKline's highly potent PDE IVb inhibitor 1 were developed. The suggested approach is based on reductive domino transformations of 3-β-carbomethoxyethyl-substituted six-membered cyclic nitronates, which are easily accessed by a stereoselective [4 + 2] cycloaddition of an appropriate nitroalkene to vinyl ethers. In vitro studies of PDE IVb inhibition by enantiomeric pyrrolizidinones (+)-1 and (-)-1 were performed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclization
  • Molecular Structure
  • Phosphodiesterase 4 Inhibitors / chemical synthesis*
  • Phosphodiesterase 4 Inhibitors / chemistry*
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry*
  • Pyrrolidinones / chemistry*
  • Pyrrolidinones / pharmacology

Substances

  • (-)-7-(3-(cyclopentyloxy)-4-methoxyphenyl)hexahydro-3H-pyrrolizin-3-one
  • Phosphodiesterase 4 Inhibitors
  • Pyrroles
  • Pyrrolidinones