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.

中文翻译：

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顺式融合的4-氨基四氢吡喃类化合物向可能的神经元受体配体的前体的三组分，非对映选择性普林斯-里特反应。

在这里，我们报道了三元偶联反应中醛，均烯丙基醇和腈的空前，高度非对映选择性的Prins-Ritter反应，用于合成四顺式取代的4-酰胺基四氢吡喃。在这项研究中，该反应不仅适用于基于碳水化合物的杂环，而且适用于更复杂的杂环，显示出可接受的转化率水平（42-97％BRSM）和排他的非对映选择性。此外，后者的杂三环被转化为我们的神经元受体配体IKM-159和MC-27的九个类似物。小鼠脑室内注射的体内试验表明，新型类似物C9处的取代基会干扰与AMPA受体的分子相互作用，它最初是在IKM-159和GluA2配体结合结构域的复合物中观察到的。因此，我们的研究表明，多组分偶联反应可用于制备结构多样的化合物，从而研究具有生物活性的小分子的构效关系。