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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.

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

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/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.

PMID:
23462714
DOI:
10.1016/j.bmc.2013.01.038
[Indexed for MEDLINE]
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