【作者】 程谋诺；

【导师】 龚流柱；

【作者基本信息】 中国科学技术大学 ， 有机化学， 2011， 博士

【摘要】 手性3, 3′-氮环螺环氧化吲哚结构单元是大量生物碱和生物活性分子的核心部分。一方面,这些天然产物奇特的结构使它们成为有机化学家的合成目标;另一方面,药物化学家根据天然产物设计新的分子以期发现新的药物分子。因此发展高效合成这类分子的不对称方法学有重要意义。本文主要介绍了利用两种不对称催化的方法直接或间接构建手性3, 3′-氮环螺环氧化吲哚体系。不对称催化1,3-偶极环加成反应是构建结构多样的四氢吡咯衍生物的重要方法,但双取代端烯参与的1,3-偶极环加成反应研究很少。本文报道了手性布朗斯特酸催化的亚胺叶立德和双取代端烯之间的1, 3-偶极环加成反应,高选择性的得到手性的四氢吡咯环。我们将得到的多取代手性四氢吡咯化合物通过硝基还原/分子内内酰胺化得到手性3, 3′-四氢吡咯螺环氧化吲哚,实现了两个spirotryprostatin A的非对映异构体的全合成。通过生物测试发现对于MD MBA468乳腺癌细胞,两个异构体和天然产物表现出相当的生物活性,由此推测绝对构型(C9和C18)不是该系列分子构效关系的关键因素。将金属催化和有机小分子催化结合发展新的有价值的反应已经成为有机转化很有潜力的策略。该策略还有节约能源,减少溶剂排放等绿色化学优点,引起有机化学家们的广泛注意。本文首次实现了用有机小分子和金属配合物结合的方法催化制备了手性3, 3′-四氢哌啶螺环氧化吲哚。反应首先发生3-取代氧化吲哚和亚胺的Mannich反应,然后在对甲苯磺酸的协助下由金(I)催化发生分子内氨化关环。系统研究发现由1,2-二苯乙二氨衍生的催化剂5.5e和PPh3AuNTf2是该反应的最佳催化剂。该反应能够得到中等的收率和最高达97%的对映选择性。更多还原

【Abstract】 The chiral spiro[nitrogencycle-3,3’-oxindole] unit constitutes a core structural element prevalent in a large family of natural products or biological active molecules On one hand, the unique structure of these natural compounds has attracted much attention from synthetic chemists; on the other hand, the significant biological activity has intrigued intense interest in the development of biologically promising analogues with improved efficiency and selectivity. Catalytic asymmetric methods to access these compounds would be highly valuable. In this manuscript, we have developed two new approaches for catalytic asymmetric synthesis of optically active derivatives containing the spiro[nitrogencycle-3,3’-oxindole] unit, respectively.The asymmetric 1, 3-dipolar cycloaddition of azomethine ylides to alkene represents an efficient and atom-economic method for enantioselective synthesis of pyrrolidine derivatives. However, methyl 2-(2-nitrophenyl)acrylate and its analogues were seldom successfully involved in highly enantioselective catalytic variants. In this manuscript, we have described a chiral Br?nsted acid-catalyzed 1,3-dipolar cycloaddition reaction of methyl 2-(2-nitrophenyl)acrylate with azomethine ylides, yielding highly enantioenriched pyrrolidine derivatives, which can be readily transformed to spiro[pyrrolidin-3,3’-oxindole] unit by easily operative reactions. The methodology holds great potential in total synthesis as demonstrated by its applications to the synthesis of diastereoisomers of spirotryprostatin A. The biological evaluation suggested that the configuration of the stereogenic center of spirooxindole (C9 and C18) was not the key element affecting the anti-cancer biological activity of spirotryprostatin alkaloids.The concept of combining transition metal catalysis and organocatalysis has emerged as a promising strategy for developing new and valuable reactions, and has attracted considerable attention as it hold great potential in the creation of new transformations, which each type of catalysts failed to afford alone. The strategy also provides a powerful tool for saving both energy and resources. In this manuscript, we have presented a highly enantioselective synthesis of spiro[4H-pyrilindin-3,3’-oxindole] derivatives via Mannich reaction of 3-substituted oxindoles and N-Boc-imines followed by intramolecular hydroamination catalyzed by a gold(I) complex with the assistance of a Br?nsted acid additive in one pot. Through systemic study, we found that the combined catalysts with a chiral 1,2- diphenylethylene-diamine skeleton 5.5e and PPh3AuNTf2 were the best catalysts of the reaction. Under the optimized reaction conditions, middle yield and excellent levels of enantioselectivity could be obtained.更多还原