title: Oxa-Pictet-Spengler reaction as key step in the synthesis of novel σ receptor ligands with 2-benzopyran structure.
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.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Knappmann
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Westfälische Wilhelms-Universität Münster, Germany. Electronic address: wuensch@uni-muenster.de.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006168:Guinea Pigs; D008024:Ligands; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001578:Benzopyrans; D008024:Ligands; D010880:Piperidines; D017480:Receptors, sigma; D013141:Spiro Compounds; C032727:piperidine
keywords: 2-Benzopyrans; Aryl-N-distance; Intramolecular Oxa-Pictet–Spengler reaction; Oxa-Pictet–Spengler reaction; Spirocyclic piperidines; Tricyclic systems; σ ligands