title: Improvement of σ1 receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones.
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.
authors: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen, Wilhelms-Universität Münster, Hittorfstraße 58-62, D-48149 Münster, Germany.
authors: Christina
authors: C
authors: Meyer
authors: Benedikt
authors: B
authors: Neue
authors: Dirk
authors: D
authors: Schepmann
authors: Shuichi
authors: S
authors: Yanagisawa
authors: Junichiro
authors: J
authors: Yamaguchi
authors: Ernst-Ulrich
authors: EU
authors: Würthwein
authors: Kenichiro
authors: K
authors: Itami
authors: Bernhard
authors: B
authors: Wünsch
mesh_terms: D000818:Animals; D006168:Guinea Pigs; D057927:Hydrophobic and Hydrophilic Interactions; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology; D000097605:Sigma-1 Receptor
chemical_list: D007783:Lactones; D017480:Receptors, sigma; D013141:Spiro Compounds; D013876:Thiophenes; D000097605:Sigma-1 Receptor