Send to:

Choose Destination
See comment in PubMed Commons below
Bioorg Med Chem. 2013 Apr 1;21(7):1844-56. doi: 10.1016/j.bmc.2013.01.038. Epub 2013 Jan 31.

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

Author information

  • 1Institut für Pharmazeutische und Medizinische Chemie der Westfälischen, Wilhelms-Universität Münster, Hittorfstraße 58-62, D-48149 Münster, Germany.


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/Ag2CO3, 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.

Copyright © 2013 Elsevier Ltd. All rights reserved.

[PubMed - indexed for MEDLINE]

LinkOut - more resources

Full Text Sources

Chemical Information

PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Write to the Help Desk