Oxa-Pictet-Spengler reaction as key step in the synthesis of novel σ receptor ligands with 2-benzopyran structure

Bioorg Med Chem. 2016 Sep 15;24(18):4045-4055. doi: 10.1016/j.bmc.2016.06.046. Epub 2016 Jun 25.

Abstract

The Oxa-Pictet-Spengler reaction of methyl 3-hydroxy-4-phenylbutanoate (8) was explored to obtain novel σ receptor ligands. 1-Acyl protected piperidone ketals 10 and 11 reacted with phenylethanol 8 to yield spirocyclic compounds. Aliphatic aldehyde acetals 19 provided 1,3-disubstituted 2-benzopyrans 20 with high cis-diastereoselectivity. The intramolecular Oxa-Pictet-Spengler reaction of 24 led to the tricyclic compound 25. The spirocyclic compounds 18 show high σ1 affinity (Ki 20-26nM) and σ1/σ2 selectivity (>9-fold), when a large substituent (n-octyl, benzyl, phenylpropyl) is attached to the piperidine N-atom. Opening of the piperidine ring to yield aminoethyl (22, 23) or aminomethyl derivatives (21) resulted in reduced σ1 affinity and σ1/σ2 selectivity.

Keywords: 2-Benzopyrans; Aryl-N-distance; Intramolecular Oxa-Pictet–Spengler reaction; Oxa-Pictet–Spengler reaction; Spirocyclic piperidines; Tricyclic systems; σ ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzopyrans / chemical synthesis
  • Benzopyrans / chemistry*
  • Benzopyrans / pharmacology*
  • Guinea Pigs
  • Ligands
  • Piperidines / chemical synthesis
  • Piperidines / chemistry*
  • Piperidines / pharmacology*
  • Rats
  • Receptors, sigma / antagonists & inhibitors
  • Receptors, sigma / metabolism*
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology

Substances

  • Benzopyrans
  • Ligands
  • Piperidines
  • Receptors, sigma
  • Spiro Compounds
  • piperidine