串联不对称还原胺化-分子内环化直接合成手性NH内酰胺

DIRECT SYNTHESIS OF CHIRAL NH LACTAMS BY ASYMMETRIC REDUCTIVE AMINATION-CYCLIZATION CASCADE REACTIONS

张瑶

11849263

硕士

化学工程领域工程

殷勤

2020-06-02

2020-07-20

哈尔滨工业大学

深圳

具有轴手性联芳基氮杂七元环的化合物有着特殊的桥连骨架，含有这类结构的化合物往往具有生理活性，因此广泛地存在于天然产物和药物分子中；同时，该结构也经常作为有机小分子催化剂和手性配体中的重要片段被应用于不对称催化。因此对这类结构新颖的分子开展不对称合成研究工作，不仅可能打开手性胺药物研发的新窗口，同时有助于开发出具有新型骨架的有机小分子催化剂或者手性配体，为不对称有机合成做出贡献。目前对于这类具有轴手性的联芳基氮杂七元环化合物的催化合成研究报道非常少，因此发展高效简洁的不对称催化的方法合成该类型化合物变得尤为紧迫。为了解决这一问题，本文主要研究了过渡金属钌催化的联芳基酮酯和铵盐的直接不对称还原胺化–环化串联反应。具体内容包括：通过2-（甲氧羰基）苯硼酸（或2-乙酰基苯硼酸）与溴代苯乙酮（或溴代苯甲酸甲酯）进行Suzuki偶联反应合成底物联芳基酮酯；在联芳基酮酯为底物，醋酸铵（NH4OAc）为胺源，氢气作还原剂，过渡金属钌与手性双膦配体的络合物为催化剂的条件下进行不对称还原胺化–环化串联反应。实验结果表明该方法可以在较为温和的实验条件下实现联芳基酮酯的不对称转化，得到同时具有中心手性和轴手性的联芳基七元环内酰胺化合物。该方法操作简单、原子经济性高并且对底物官能团的容忍程度高，大部分测试的化合物都可以获得较高的产率，最高可达98%；同时还可以获得优秀的对映体过量值，最大可大于99%；为了展示此方法的合成价值，对合成的轴手性联芳基七元环内酰胺类化合物的衍生化进行了研究，研究包括对内酰胺羰基官能团的进一步衍生转化为其他基团以及利用本文的方法对具有相似结构且具有生物活性的分子进行合成。

Biaryl aza-seven-membered ring compounds with an axial chirality have a special bridging skeleton, a structure that usually exists in molecules with physiological activity, and is widely incorporated into the synthesis of potentially pharmaceutical molecules; in the same time, this structure also serves as an important subunit for small-molecule organocatalysts and chiral ligands used in asymmetric catalysis. Therefore, the asymmetric synthetic research on these molecules with such a novel structure may open a new window for the development of chiral amine drugs, and in the meanwhile help to develop novel organo-catalysts and chiral ligands, which may contribute to further development of the field of asymmetric catalysis. At present, there are very few reports on the catalytic synthesis of biaryl aza-seven-membered ring compounds with an axial chirality. Therefore, it is highly desirable to develop highly efficient and concise asymmetric synthesis of this type of compounds.In order to solve this problem, this thesis mainly studies the asymmetric reductive amination-cyclization cascade reaction of biaryl ketoneester catalyzed by ruthenium complex in the presence of ammonium salts. The detailed contents mainly include: syntheses of the substrate biaryl ketone esters through the Suzuki coupling reaction; study of the asymmetric reductive amination-cyclization cascade reaction of biaryl ketone esters with ruthenium complexes ligated with a chiral bisphosphine ligand as catalysts, ammonium acetate as the ammonia source and H2 as the reductant. The experimental results have proved that this method can achieve asymmetric transformations of biaryl ketone esters under relatively mild conditions, leading to the synthesis of biaryl seven-membered ring lactams containing a central chirality and axial chirality. The method features simple operation, high atomic economy, good tolerance to various functional groups. Most of the tested substrates could reach up to 98% yield and >99% ee; to showcase the potential application of this methodology, further derivatization of the axially chiral biaryl seven-membered ring lactams is also investigated.

还原胺化 手性内酰胺 轴手性 串联 钌

reductive amination chiral lactam axial chirality cascade ruthenium

中文

联合培养

南方科技大学

张瑶. 串联不对称还原胺化-分子内环化直接合成手性NH内酰胺[D]. 深圳. 哈尔滨工业大学,2020.