Catalytic Castagnoli--Cushman reaction-based synthesis of tetrahydroisoquinolone--glutarimide dyads and their evaluation as potential cereblon ligands

A series of imines derived from α-aminoglutarimide and alhehydes RCHO was introduced into the In(OTf)<sub>3</sub>-catalyzed Castagnoli--Cushman reaction with homophthalic anhydrides thus yielding novel glutarimide--tetrahydroisoquinolone dyads with moderate yields. Carrying out the reaction at room temperature affords isomers with <em>cis</em>-orientation of the R substituent and carboxy group whereas heating to 80 °C promotes conversion into more stable <em>trans</em>-isomers. Some selected compounds were evaluated <em>in vitro</em>, revealing mild or no antiproliferative effects, and tested for cereblon-binding, with the bestperforming compound showing an affinity in the range of canonical cereblon ligands.