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

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 alpha-arylation of the thiophene moiety was performed with the catalytic system PdCl2/2,2'-bipyridyl/Ag2CO3, whereas the beta-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 alpha-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 sigma(1) affinity compared to the non-arylated parent compounds. A phenyl moiety at the 'left' position (2'-position in 20a) also increased the sigma(1) affinity but to a lower extent. A considerable reduction of sigma(1) 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 sigma(1) 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. (C) 2013 Elsevier Ltd. All rights reserved.