手性4,5-二取代-2-哌啶酮砌块的合成

发布时间：2018-04-13 03:38

本文选题：4 + 5-二取代-2-哌啶酮　；参考：《重庆大学》2014年硕士论文

【摘要】：手性4,5-二取代-2-哌啶酮化合物是一类C4、C5取代的含羰基的六元哌啶杂环化合物，其作为手性合成子不仅能够合成多种具有药理活性和生物活性的哌啶衍生物，同时还能通过化学转化，制备多种药用天然产物，如抗抑郁药帕罗西丁，细胞毒性和钙调素拮抗剂Pseudodistomin A、B，和降血压药物利血平等。另外手性4,5-二取代-2-哌啶酮由于结构中含多个官能基，可以通过发生C2羰基还原、C3烯醇烷基化、C4芳基化、C5碳链延长反应等构建更复杂的骨架，因而在合成上具有广泛的应用价值。本论文以邻苯二甲酰胺保护的化合物70为原料，运用Evans教授发展的VA唑烷酮诱导的烯醇烷基化反应引入C5位手性中心制备化合物72a；化合物72a经7步反应制备了醛107，并随即与乙酸甲酯发生Aldol反应延长一个碳链形成化合物109；化合物109发生内酰胺反应分别以14步、22%和21%的总收率制备了4,5-二取代-2-哌啶酮1和2。中间体1和2通过硅胶柱进行纯化分离。经手性柱分析1和2，我们发现其为消旋体，说明醛107在碱作用下α位极易消旋，造成化合物1和2的C5位发生消旋。在本论文中，我们也对消旋化的可能机理进行了讨论。
[Abstract]:Chiral 4o 5-disubstituted -2-piperidinone compounds are a class of C4C5-substituted hexagonal piperidine heterocyclic compounds. As chiral synthesizers, they can not only synthesize many kinds of piperidine derivatives with pharmacological and biological activities.At the same time, many kinds of medicinal natural products can be prepared by chemical transformation, such as paroxetine, cytotoxicity and calmodulin antagonist Pseudodistomin Afib, and antihypertensive drug reserpine.In addition, chiral 4o 5- disubstituted -2-piperidinone has many functional groups in its structure, so it can be used to form a more complex skeleton by C _ 2 carbonyl reductive C _ 3 enol alkylation, C _ 4 arylation of C _ 4 aromatization and C _ 5 C _ 5 chain prolongation.Therefore, it has wide application value in synthesis.In this paper, phthalamide protected compound 70 was used as raw material.The alkylation of enol induced by VA azolone developed by Professor Evans was introduced into the chiral center of C 5 to produce 72a, and compound 72a was prepared by 7 steps reaction, and then extended a carbon chain by Aldol reaction with methyl acetate.Compound 109 was synthesized by lactam reaction of compound 109 in the total yield of 14 steps 22% and 21% respectively to prepare 4o 5-disubstituted -2-piperidinone 1 and 2.Intermediates 1 and 2 were purified by silica gel column.By analyzing 1 and 2 by chiral column, we found that they are racemes, indicating that aldehydes 107 are easily racemic at the 伪 position under the action of alkali, which results in the racemization of C 5 of compounds 1 and 2.In this paper, we also discuss the possible mechanism of racemization.
【学位授予单位】：重庆大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

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