Oxa-Pictet-Spengler reaction as key step in the synthesis of novel σ receptor ligands with 2-benzopyran structure

详细信息    查看全文

• 作者：Inga Knappmann^a ; Dirk Schepmann^a ; Bernhard Wü ; nsch^a ; ^b ; ^{wuensch@uni-muenster.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：σ ligands ; Oxa-Pictet&ndash ; Spengler reaction ; Intramolecular Oxa-Pictet&ndash ; Spengler reaction ; 2-Benzopyrans ; Spirocyclic piperidines ; Tricyclic systems ; Aryl-N-distance
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 September 2016
• 年：2016
• 卷：24
• 期：18
• 页码：4045-4055
• 全文大小：783 K

文摘

The Oxa-Pictet–Spengler reaction of methyl 3-hydroxy-4-phenylbutanoate (8) was explored to obtain novel σ receptor ligands. 1-Acyl protected piperidone ketals 10 and 11 reacted with phenylethanol 8 to yield spirocyclic compounds. Aliphatic aldehyde acetals 19 provided 1,3-disubstituted 2-benzopyrans 20 with high cis-diastereoselectivity. The intramolecular Oxa-Pictet–Spengler reaction of 24 led to the tricyclic compound 25. The spirocyclic compounds 18 show high σ₁ affinity (K_i 20–26 nM) and σ₁/σ₂ selectivity (>9-fold), when a large substituent (n-octyl, benzyl, phenylpropyl) is attached to the piperidine N-atom. Opening of the piperidine ring to yield aminoethyl (22, 23) or aminomethyl derivatives (21) resulted in reduced σ₁ affinity and σ₁/σ₂ selectivity.