生物碱alstocholarine和daphenylline的不对称合成研究

	生物碱alstocholarine和daphenylline的不对称合成研究
	姚建能
导师	杨玉荣
关键词	不对称合成，虎皮楠生物碱，单萜吲哚生物碱，天然产物 asymmetric synthesis, daphniphyllum alkaloids, monoterpenoid indole alkaloid, natural product
摘要	论文由三章组成，第一章论述了氮杂二环[3.3.1]壬烷骨架的合成研究进展。第二章阐述了铱 / 胺双元催化烯丙基化不对称合成单萜吲哚生物碱 (-)- alstocholarine。第三章重点介绍虎皮楠生物碱(-)-daphenylline 的合成研究，运用过渡金属催化形成碳-碳键和 1,3-偶极环加成/消除串联反应来构建氮杂二环 [3.3.1]壬烷核心骨架。第一章综述了氮杂二环[3.3.1]壬烷骨架的构建方法，主要依据最后关环构筑骨架的成键方式进行分类，可以分为 C1-N 成键关环、 N-C3 成键关环、 C3-C4 成键关环、 C4-C5 成键关环、 C5-C6 成键关环、 C6-C7 成键关环、 C8-C1 成键关环，并以天然产物全合成为例子进行阐述。此外，也讨论了催化不对称合成氮杂二环 [3.3.1]壬烷骨架。第二章阐述了单萜吲哚生物碱(-)-alstocholarine 的不对称合成研究。生物碱 (-)-alstocholarine 具有氮杂二环[3.3.1]壬烷的骨架，骨架的一侧是吲哚，另外一侧是吡咯环。以吲哚烯丙基二级醇和线性醛为起始原料，采用铱/胺双元催化为关键步骤完成 γ,δ-不饱和醛底物的制备。其它的关键反应包括：利用 Nicolaou 发展的方法引入 2-羰基吡咯单元，官能团的转换得到醛并运用 DBU 促进的分子内 6- exo-trig 环化形成缩醛胺，得到四环骨架，最后通过 Tf2O 促进的分子内 PictetSpengler 环化完成氮杂二环[3.3.1]壬烷桥环的构建，同时形成了(-)-alstocholarine 的五环骨架。第三章重点阐述了虎皮楠生物碱(-)-daphenylline 的不对称全合成研究。 (-)- daphenylline 是虎皮楠家族中唯一含有苯环结构的生物碱。本论文从简单的苯基的烯丙基二级醇出发，经铱/胺的双元催化构建起始的两个连续手性中心，然后经 Suzuki 偶联反应延伸异丙烯基碳链， RCM 反应形成三取代的烯烃构建 6/6 二环骨架， Mitsunobu 反应引入叠氮，立体控制的叠氮与烯烃的分子内 1,3-偶极环加成/消除 N2 串联反应形成氮杂二环[3.3.1]壬烷桥环骨架。接着经钯催化锡试剂对炔的 syn 式加成，锡碘交换得到 Heck 反应的底物，分子内还原 Heck 反应(5-exo trig 环化，高立体选择性和区域选择性)构建全碳的季碳中心，形成 6/6/6/5 四环体系。分子内 Friedel-Crafts 酰化分别关七元环和五元环系，得到(-)-daphenylline的六环骨架，最后经氧化态的调整，完成(-)-daphenylline 的形式合成。; The dissertation herein is presented in three chapters. In the first chapter, the synthetic methodologies for forming 2-azabicyclo[3.3.1]nonane framework are reviewed. The second chapter describes the catalytic, enantioselective synthesis of monoterpenoid indole alkaloid (-)-alstocholarine enabled by iridium-amine dual catalyzed allylation. The last chapter elaborates on the formal synthesis of daphniphyllum alkaloid (-)-daphenylline, leveraging transition-metal catalysis to form carbon-carbon bonds and 1,3-dipolar cycloaddition/elimination cascade to afford bridged azabicyclic [3.3.1] nonane core. The first chapter surveys an overview of synthetic methods to forge a unique 2- azabicyclo[3.3.1]nonane scaffold. This review summarizes seven strategies defined by forming the last C-C bond or C-N bond to afford pivotal 2-azabicyclo[3.3.1]nonane cores. Namely, these strategies are listed as C1-N, N-C3, C3-C4, C4-C5, C5-C6, C6- C7, and C8-C1 bond formations. Each strategy is exemplified with selected total synthesis of complex natural products, highlighting synthetic studies of 2- azabicyclo[3.3.1]nonanes. Additionally, it briefly discussed catalytic, enantioselective synthesis of 2-azabicyclo[3.3.1]nonanes. The second chapter describes the catalytic, enantioselective formal synthesis of (-)-alstocholarine. The monoterpenoid indole alkaloids alstocholarines share an atypical pentacyclic backbone containing the 2-azabicyclo[3.3.1]nonanes accompanied by an indole motif on one side and a pyrrole ring on the other side. The main building block is enabled by catalytic, asymmetric synthesis of γ,δ-unsaturated aldehyde embracing two vicinal tertiary stereogenic centers derived from indole-based allylic alcohol and linear aldehyde substrate. The elaboration of the 2-ketopyrrole moiety is established by Nicolaou’s method of constructing the tricyclic architecture. Functional group transformations implemented in this synthesis afford an advanced intermediate aldehyde, which undergoes DBU-mediated 6-exo-trig cyclization to form a hemiaminal product, giving the tetracyclic backbone. The pentacyclic scaffold of (-)-alstocholarine is achieved by Tf2O-promoted Pictet-Spengler reaction, and 2-azabicyclo[3.3.1]nonane core embedded in the scaffold is thus completed. The last chapter focuses on the asymmetric synthesis of daphniphyllum alkaloid (-)-daphenylline. The flagship member of daphniphyllum alkaloids, daphenylline, stands out from its siblings because it is the unique one that contains a tetrasubstituted benzene ring. The iridium and amine dual catalysis to access the building block with vicinal stereocenters is regarded as a linchpin of the synthesis. Other notable transformations include a Suzuki cross-coupling to install the isopropenyl group, ringclosing metathesis (RCM) reaction to construct the 6/6 membered bicyclic core containing trisubstituted double bond, a Mitsunobu reaction to form azide, a stereocontrolled 1,3-dipolar cycloaddition/elimination cascad
语种	中文
	2022-05
学位授予单位	中国科学院大学
文献类型	学位论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75208
专题	昆明植物所硕博研究生毕业学位论文
推荐引用方式 GB/T 7714	姚建能. 生物碱alstocholarine和daphenylline的不对称合成研究[D]. 中国科学院大学,2022.

条目包含的文件
文件名称/大小	文献类型	版本类型	开放类型	使用许可
姚建能-博士学位论文Plain_text（7993KB）	学位论文		限制开放	CC BY-NC-SA	请求全文