Design and Synthesis of Azacyclophanes

氮杂环蒽是一种适合于水溶液中客体络合的宿主化合物。人们研究了各种类型的氮杂环番，但尚未合成出5-氮杂环苄基衍生物。我们已经制备了具有独特的C_2对称结构的5-硅环苄基化合物。因此，季铵盐（N，N-二烷基-5-氮杂环苯）有望作为一种手性相转移催化剂。另一方面，关于氮杂环霉素生物活性的研究迄今尚未见报道。我们尝试通过两种途径构建5-氮杂环苯骨架。一开始，我们利用一种有用的合成嵌段——双（6-溴代戊甲酰基）藜芦醇在钯催化剂的存在下与苯胺反应构建目标骨架，但无法得到5-氮杂环苯基衍生物。第二种方法是使用双（2-羟基-甲基苯基）胺作为起始原料。4-氯-2-（2-羟甲基苯基）氨基苯甲醇，易由苯甲酰胺【〇！R】，在酸性条件下用veratrole处理，成功得到5-氮杂环苯衍生物(1)。与过量的veratrole反应得到一种无环双（veratylphenyl）胺，并在酸性条件下与福尔马林环合成环四苄，意外生成双环环烷。该产品的结构尚未披露。双（戊基苯基）胺经福尔马林和NaBH_4甲基化得到相应的n -甲基衍生物，目前正在进行环化。圆盘法对5种真菌均无抑菌活性。采用Irwin法对ddY品系5周小鼠进行行为学研究。结果，在注射环胺期间观察到扭曲(1)。

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).