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 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.