Design and Synthesis of Azacyclophanes

氮杂环芳是一种适用于水溶液中客体络合的主体化合物。各种类型的氮杂环芳已被研究，然而，5-氮杂环苯亚甲基衍生物尚未被合成。我们已经合成了具有独特的C_2对称结构的5-硅环亚苄基化合物。因此，季铵盐（N，N-二烷基-5-氮杂环亚苄基）有望用作手性相转移催化剂。另一方面，关于氮杂环蕃类化合物的生物活性研究至今未见报道。我们尝试通过两种途径构建5-氮杂环亚苄基骨架。首次采用双（6-溴藜芦基）藜芦醚（bis（6-bromo veratryl）veratrole）作为手性嵌段，在钯催化下与苄胺反应构建目标骨架，但未能得到5-氮杂环苯亚甲基衍生物。第二种策略涉及使用双（2-羟基-甲基苯基）胺作为起始材料。4-氯-2-（2-羟甲基苯基）氨基苄醇，易于从氯苯啼啶[○！R]在酸性条件下与藜芦醇反应，成功地得到5-氮杂环苯亚甲基衍生物（1）。与过量藜芦醚反应得到无环双（藜芦基苯基）胺，在酸性条件下用福尔马林将其环化为环四亚苄基，尝试意外地形成双环环番。该产品的结构尚未披露。用甲醛和NaBH_4对双藜芦基苯胺进行甲基化反应，得到相应的N-甲基衍生物，环合反应正在进行中。用纸片法测得氮杂环蕃（1）对五种真菌均无抑菌活性。根据欧文的方法在ddY品系5周龄小鼠中研究行为。结果，注射环胺（1）期间观察到扭体。

Azacyclophanes are host compounds suitable for complexation of guest in aqueous solution. Various type of azacyclophanes were investigated, however, 5-azacyclobenzylene derivatives have not been synthesized. We have already prepared 5-silacyclobenzylene compounds, which have a unique C_2 symmetrical structure. Therefore, a quatemary ammmonium salt (N,N-dialkyl-5-azacyclobenzylene) is promissing to be used as a chiral phase transfer catalyst. On the other hands, studies on biological activities of azacyclophanes have not been reported so far. We tried to construct the 5-azacyclobenzylene skeleton by two pathways. At first bis(6-bromoveratryl)veratrole, a useful synthestic block, was apllied to react with benzyl amine in the presence of palladium catalyst to construct the target skeleton, however, it failed to obtain 5-azacyclobenzylene derivatives. Second tactics involved employment bis(2-hydroxy-methylphenyl)amine as a starting material. 4-Chlro-2-(2-hydroxymethylphenyl)aminobenzyl alcohol, readily prepared from Lobenzarid【○!R】, was treated with veratrole under acidic conditions to give successfully 5-azacyclobenzylene derivative (1). The reaction with excess veratrole afforded an acyclic bis(veratrylphenyl)amine, cyclization of which into cyclotetrabenzylene with formalin under acidic conditions was tried to form bicyclic cyclophane unexpectedly. The structure of the product was not disclosed yet. The bis(veratryl-phenyl)amine was methylated with formalin and NaBH_4 to give the corresponding N-methyl derivative, cyclization of which is now in progress. No antifungal activity of azacyclophane (1) to five types of funngi was observed by the disc method. Behaviors were investigated according to Irwin's method in ddY strain 5 week mice. As a result, writhing was observed during by the injection with the cyclic amine (1).