Three-component, diastereoselective Prins-Ritter reaction for cis-fused-4-amidotetrahydropyrans toward precursor for possible neuronal receptor ligands.

Here we report an unprecedented, highly diastereoselective Prins-Ritter reaction of aldehydes, homoallyic alcohols, and nitriles a three-component coupling reaction for synthesis of tetra-cis-substituted 4-amidotetrahydropyrans. In this study, the reaction was not only applied for carbohydrate-based heterobicycles, but also for more complex heterotricycles, to show the acceptable levels of conversion yield (42-97% BRSM) and exclusive diastereoselectivity. Furthermore, the latter heterotricycles were converted to nine analogs of our neuronal receptor ligands, IKM-159 and MC-27. In vivo assay by intracerebroventricular injection in mice suggested that substituent at C9 of the novel analogs interferes with the molecular interactions with the AMPA receptor, which have been originally observed in the complex of IKM-159 and GluA2 ligand binding domain. Our research has thus shown the power of multicomponent coupling reaction for preparation of a structurally diverse compound collection to study structure-activity relationships of biologically active small molecules.