Asymmetric Reactions by the Use of Pyridinophane with Planar Chirality

烟酰胺腺嘌呤二核苷酸（Nicotinamide-adenine dinucleotide， NAD）是生物系统中参与许多氧化还原反应的重要辅酶。设计了具有平面手性的副吡啶衍生物作为辅酶的模型化合物，研究了高立体选择性的有机反应。研究了吡啶烷的合成、光学拆分及其在苯甲酰甲酸乙酯不对称还原中的应用。以2,5-二（溴乙基）-3-乙氧基羰基吡啶和1,4-二（巯基）苯为偶联剂，合成了副吡啶衍生物8-乙氧基羰基[2](2,5)-吡啶。以51%的收率得到相应的二硫烷，然后以94%的收率与间氯丁苯甲酸氧化得到相应的二砜。通过对反应条件的详细研究，对二砜进行闪蒸真空热解，得到了产率为53%的副吡啶衍生物。对吡啶酚衍生物进行光学拆分，发现用手性柱的高效液相色谱可以得到期望的光学活性对吡啶酚，并与手性1-苯乙胺转化为酰胺后分离为非对映体。然后用碘化甲酯n -甲基化，再用二亚硝酸钠还原，得到相应的二氢吡啶衍生物。用这些二氢吡啶衍生物研究了苯甲酰甲酸乙酯的还原反应。然而，反应没有进行，原料被回收。为了研究反应没有发生的原因，合成了另一种结构张力较小的二氢吡啶二酚。采用类似的反应方案，得到了8-乙氧羰基[3]对环[3](2,5)-吡啶番烷。光学分辨率和衍生化到相应的二氢吡啶衍生物将在适当的时候进行研究。虽然目前还没有利用对吡啶烷的NADH模型化合物实现苯甲酰甲酸乙酯的不对称还原，但本研究建立了对吡啶烷衍生物的合成路线。这些化合物的合成用途将在未来进行报道。少

Nicotinamide-adenine dinucleotide (NAD) is an important coenzyme involved in many oxidation and reduction reactions in biological system. Parapyridinophane derivatives having planar chirality was designed as model compounds of the coenzyme to investigate a highly stereoselective organic reactions. A synthesis and optical resolution of the pyridinophane and its use in asymmetric reduction of ethyl benzoylformate was examined in this study.The synthesis of a parapyridinophane derivative, 8-ethoxycarbonyl[2]paracyclol[2] (2,5)-pyridinophane, was started from a coupling reaction of 2,5-bis (bromomethyl)-3-ethoxy-carbonylpyridine and 1,4-bis-(mercaptomethyl) benzene. The corresponding dithiaphane was obtained in 51% yield and it was then oxidized to the corresponding disulfone in 94% yield with m-chloroperbanzoic acid. The flash vacuum pyrolysis of the disulfone afforded the desired parapyridinophane derivative in 53% yield after detailed study of the reaction conditions of the pyrolysis. T … More hen the pyndinophane derivative was subjected to optical resolution and it was found that the resolution was achieved by HPLC using a chiral column to afford the desired optically active parapyridinophane, It was also separated as diastereomers after converting to amide with chiral 1-phenylethylamine. The parapyridinophanes were then derived to the coresponding dihydropyridine derivatives by N-methylation with methyl iodide followed by reduction with sodium dithionite. Reduction of ethyl benzoylformate was examined by using these dihydropyridine derivatives. However, the reaction did not proceeded and the starting material was recovered. To examine the reason that the reaction did not take place, a synthesis of another dihydropyridinophane with less strained structure was carried out. 8-Ethoxycarbonyl [3] paracyclo [3] (2,5)-pyridinophane was obtained in racemic form by using the similar reaction scheme. The optical resoluton and derivatization to the corresponding dihydropyridine derivative will be examined in due course.Although the asymmetric reduction of ethyl benzoylformate has not yet been realized using NADH model compounds of parapyridinophane, the synthetic route for para-pyridinophane derivative was established by this study. The synthetic utility of these compounds will be reported in the future. Less