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Three-Component, Diastereoselective Prins–Ritter Reaction for cis-Fused 4‑Amidotetrahydropyrans toward a Precursor for Possible Neuronal Receptor Ligands

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journal contribution
posted on 10.05.2016, 00:00 by Manami Chiba, Yuichi Ishikawa, Ryuichi Sakai, Masato Oikawa
Here, we report an unprecedented, highly diastereoselective Prins–Ritter reaction of aldehydes, homoallylic alcohols, and nitriles in a three-component coupling reaction for the 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, showing acceptable levels of conversion yield (42–97% BRSM) and exclusive diastereoselectivity. Furthermore, the latter heterotricycles were converted to nine analogues of our neuronal receptor ligands IKM-159 and MC-27. An in vivo assay by intracerebroventricular injection in mice suggested that the substituent at C9 of the novel analogues interferes with the molecular interactions with the AMPA receptor, which was originally observed in the complex of IKM-159 and the GluA2 ligand binding domain. Our research has thus shown the power of a multicomponent coupling reaction for the preparation of a structurally diverse compound collection to study structure–activity relationships of biologically active small molecules.

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