Improvement of σ1 receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones
Improvement of σ1 receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones
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DOI：
10.1016/j.bmc.2013.01.038
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发表时间：
2013-04-01
影响因子：
3.5
通讯作者：
Wuensch, Bernhard
中科院分区：
文献类型：
--
作者：
Meyer, Christina;Neue, Benedikt;Wuensch, Bernhard
螺旋环内酯13,14和18的直接c - h键芳化允许在合成的最后一步引入不同的芳基部分。采用PdCl2/2,2′-联吡啶基/Ag2CO3催化体系对噻吩部分进行了选择性α -芳基化，而采用PdCl2/P[OCH(CF3)(2)](3)/Ag2CO3催化体系对噻吩环的β -位置进行了修饰。由于电子和空间的原因，五元内酯18的芳化发生在两个α -位置，提供4'-单-，6'-单-和4',6'-二芳化噻吩22-26a-c。与非芳基化亲本化合物相比，在左上角（上）位置增加芳基片段的化合物（1'-位置为13,3 '-位置为14,4 '-位置为18）显示出更高的sigma(1)亲和力。“左”位的苯基片段（20a中的2位）也增加了sigma(1)亲和力，但程度较低。在18的6′位置引入芳基片段后，观察到sigma(1)亲和力显著降低，这可能是由于屏蔽了叔胺，叔胺对于与sigma(1)受体相互作用至关重要。对实验结果的讨论得到了高能级量子化学dft计算13和18的nbo电荷和相关芳基化产物的相对能的支持。(C) 2013 Elsevier Ltd.版权所有。
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 alpha-arylation of the thiophene moiety was performed with the catalytic system PdCl2/2,2'-bipyridyl/Ag2CO3, whereas the beta-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 alpha-positions providing 4'-mono-, 6'-mono- and 4',6'-diarylated thiophenes 22-26a-c. Compounds with an additional aryl moiety at the 'upper left (top)' position (1'-position of 13, 3'-position of 14, 4'-position of 18) showed increased sigma(1) affinity compared to the non-arylated parent compounds. A phenyl moiety at the 'left' position (2'-position in 20a) also increased the sigma(1) affinity but to a lower extent. A considerable reduction of sigma(1) affinity was observed after introducing an aryl moiety in 6'-position of 18, which might result from shielding the tertiary amine, which is crucial for interaction with the sigma(1) 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. (C) 2013 Elsevier Ltd. All rights reserved.