Improvement of ¦Ò₁ receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones

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• 作者：Christina Meyer^a ; Benedikt Neue^b ; Dirk Schepmann^a ; Shuichi Yanagisawa^c ; Junichiro Yamaguchi^c ; Ernst-Ulrich Wü ; rthwein^b ; Kenichiro Itami^c ; ^&dagger ; ; ^{itami.kenichiro@a.mbox.nagoya-u.ac.jp} ; Bernhard Wü ; nsch^a ; ^{wuensch@uni-muenster.de}
• 关键词：¦Ò1 Ligands ; C&ndash ; H-bond arylation of complex thiophenes ; Spirocyclic lactones ; DFT calculations ; Hydrophobic pocket
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：1 April, 2013
• 年：2013
• 卷：21
• 期：7
• 页码：1844-1856
• 全文大小：810 K

文摘

The direct C-H-bond arylation of the complex spirocyclic lactones 13, 14, and 18 allows the introduction of diverse aryl moieties in the last step of the synthesis. A selective ¦Á-arylation of the thiophene moiety was performed with the catalytic system PdCl₂/2,2¡ä-bipyridyl/Ag₂CO₃, whereas the ¦Â-position of the thiophene ring was addressed by using the alternative catalytic system PdCl₂/P[OCH(CF₃)₂]₃/Ag₂CO₃. Due to electronic and steric reasons the arylation of the five-membered lactone 18 occurred in both ¦Á-positions providing 4¡ä-mono-, 6¡ä-mono- and 4¡ä,6¡ä-diarylated thiophenes 22-26a-c. Compounds with an additional aryl moiety at the ¡®upper left (top)¡¯ position (1¡ä-position of 13, 3¡ä-position of 14, 4¡ä-position of 18) showed increased ¦Ò₁ affinity compared to the non-arylated parent compounds. A phenyl moiety at the ¡®left¡¯ position (2¡ä-position in 20a) also increased the ¦Ò₁ affinity but to a lower extent. A considerable reduction of ¦Ò₁ affinity was observed after introducing an aryl moiety in 6¡ä-position of 18, which might result from shielding the tertiary amine, which is crucial for interaction with the ¦Ò₁ receptor. The discussion of the experimental results is supported by high-level quantum chemical DFT-calculations of the NBO-charges of 13 and 18 and the relative energies of the related arylated products.