Improvement of σ1 receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones

Christina Meyer, Benedikt Neue, Dirk Schepmann, Shuichi Yanagisawa, Junichiro Yamaguchi, Ernst Ulrich Würthwein, Kenichiro Itami, Bernhard Wünsch

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Abstract

The direct C-H-bond arylation of the complex spirocyclic lactones 13, 14, and 18 allows the introduction of diverse aryl moieties in the last step of the synthesis. A selective α-arylation of the thiophene moiety was performed with the catalytic system PdCl2/2,2′-bipyridyl/Ag 2CO3, whereas the β-position of the thiophene ring was addressed by using the alternative catalytic system PdCl2/ P[OCH(CF3)2]3/Ag2CO3. Due to electronic and steric reasons the arylation of the five-membered lactone 18 occurred in both α-positions providing 4′-mono-, 6′-mono- and 4′,6′-diarylated thiophenes 22-26a-c. Compounds with an additional aryl moiety at the 'upper left (top)' position (1′-position of 13, 3′-position of 14, 4′-position of 18) showed increased σ1 affinity compared to the non-arylated parent compounds. A phenyl moiety at the 'left' position (2′-position in 20a) also increased the σ1 affinity but to a lower extent. A considerable reduction of σ1 affinity was observed after introducing an aryl moiety in 6′-position of 18, which might result from shielding the tertiary amine, which is crucial for interaction with the σ1 receptor. The discussion of the experimental results is supported by high-level quantum chemical DFT-calculations of the NBO-charges of 13 and 18 and the relative energies of the related arylated products.

Original languageEnglish
Pages (from-to)1844-1856
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number7
DOIs
Publication statusPublished - 2013 Apr 1

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Keywords

  • C-H-bond arylation of complex thiophenes
  • DFT calculations
  • Hydrophobic pocket
  • Spirocyclic lactones
  • σ Ligands

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Meyer, C., Neue, B., Schepmann, D., Yanagisawa, S., Yamaguchi, J., Würthwein, E. U., Itami, K., & Wünsch, B. (2013). Improvement of σ1 receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones. Bioorganic and Medicinal Chemistry, 21(7), 1844-1856. https://doi.org/10.1016/j.bmc.2013.01.038