Exploitation of an additional hydrophobic pocket of σ receptors: Late-stage diverse modifications of spirocyclic thiophenes by C-H bond functionalization

The hypothesis that the σ receptor will tolerate an additional aryl moiety in position 1 of the spirocyclic system was based on spirocyclic pyrazole derivatives, pharmacophore models of σ receptor ligands and DFT calculations. The strategy of introducing the aryl residue at the final step of the synthesis allowed the preparation of a large set of diverse ligands for the exploitation of the hydrophobic pocket of the σ receptor protein. The catalyst system PdCl /2,2′-bipyridyl/Ag CO is able to introduce various aryl groups onto the α-positions of spirocyclic thiophene derivatives 5 and 6 to afford the target aryl-appended spirocyclic thiophenes 3 and 4. Although the σ affinity of the 1-phenyl substituted spirocyclic thiophenes 3a and 4a is slightly reduced compared with the σ affinity of the non-arylated compounds 5 and 6, both compounds represent very potent σ receptor ligands (3a: K = 4.5 nM; 4a: K = 1.0 nM). This result indicates that an aryl moiety in position 1 is well tolerated by the σ receptor protein. The substitution pattern of the additional phenyl moiety has only weak effects on the σ affinity. Even ligands 3f and 4h with extended naphthyl residue show high σ affinity. However, decrease of σ affinity by extension of the π-system to a biphenylyl substituent (4j: K = 30 nM) indicates that the biphenylyl residue is too large for the primary hydrophobic binding pocket of the σ receptor. © The Royal Society of Chemistry 2011.