生物碱(-)-Amathaspiramide F和(-)-Cephalotaxine 的不对称合成

	生物碱(-)-Amathaspiramide F和(-)-Cephalotaxine 的不对称合成
	李路路
导师	杨玉荣
关键词	Ir/Cu协同催化 Ir/Cu synergistic catalysis (-)-amathaspiramide F (-)-Amathaspiramide F (-)-cephalotaxine (-)-Cephalotaxine 不对称合成 Asymmetric synthesis
摘要	本文论述了生物碱(-)-amathaspiramide F和(-)-cephalotaxine的不对称合成研究，主要包括以下三章内容: 第一章概述了α, α-二取代的α-氨基酸（α-AAs）的结构特征以及合成此类氨基酸的各种方法。含有邻位叔碳和季碳立体中心的具有光学活性的α-AAs是许多具有生物活性的天然产物或药物的重要结构组成，王春江和张万斌等提出的Ir/Cu协同催化策略，从相同的起始原料开始，通过对两种手性催化剂进行组合可以合成全部的α-AAs的四种立体异构体，能够实现绝对构型以及相对构型的完全控制。第二章介绍了生物碱(-)-amathaspiramide F的不对称全合成。天然产物(-)-amathaspiramide F具有氮杂螺环[3,3]庚烷骨架，含三个连续的手性中心，其在C-5螺环中心连接一个吡咯环，在C-9位连接一个二溴甲氧基苯环，在C-8位含有稳定的半缩胺醛。以烯丙醇碳酸酯和亚胺作为起始原料，利用Ir/Cu协同催化作为关键步骤一步构建天然产物的两个相邻手性中心，再经过硼氢化氧化、分子内环化等反应完成其吡咯烷环的构建，之后通过形成稳定的内酯结构引入溴原子，随后胺解、氧化继而发生分子内环化构建含有半缩胺醛的环，得到单一的异构体(-)-amathaspiramide F。第三章介绍了生物碱(-)-cephalotaxine的不对称合成。(-)-cephalotaxine有三个连续的手性中心，其本身不具有药理活性，而homoharringtonine是(-)-cephalotaxine的酯，具有抗肿瘤活性，已被FDA批准用于慢性粒细胞白血病的治疗。自分离以来，围绕(-)-cephalotaxine的全合成研究有很多，但通过催化不对称的方法进行全合成研究的工作很少。我们将Ir/Cu协同催化反应应用于(-)-cephalotaxine的不对称合成，一步构建两个相邻的手性中心，随后通过RCM反应构建D环，紧接着通过几步转化、氧化态的调整，完成C环的构建，最后利用还原胺化，在酸性条件下发生分子内的傅克反应，关上七元环，得到Mori路线的中间体，再经三步转化便完成(-)-cephalotaxine的形式合成。; This thesis discusses the asymmetric total synthesis of the alkaloid (-)-amathaspiramide F and (-)-cephalotaxine, which includes the following three chapters: In chapter 1, the structural feature of α, α-disubstituted α-amino acids (α-AAs), and various methods of synthesizing such amino acids are reviewed. Optically active α-AAs, which contain the vicinal tertiary carbon and quaternary carbon stereocenters, are significant structural motifs in biologically active natural products and pharmaceuticals. The Ir/Cu synergistic catalysis proposed by Chun-Jiang Wang and Wan-bin Zhang et al. can provide a complete set of stereoisomers of α-AAs by combining the two chiral catalysts, realizing full control of the absolute and relative configuration from the same starting material. Chapter 2 depicts the asymmetric total synthesis of the alkaloid (-)-amathaspiramide F. Natural (-) - amathaspiramide F has a azaspirocyclic [3,3] heptane skeleton, which contains three consecutive chiral centers. It connects a pyrrolidine ring at the center of the C-5 spirocyclic ring, a dibromomethoxybenzene ring at the C-9 position, and a stable semi acetaldehyde at the C-8 position. With allyl carbonate and imine as the starting materials, Ir/Cu synergistic catalysis is used as the key step to construct two adjacent chiral centers of natural products in one step, and then the pyrrolidine ring is constructed through hydroboration oxidation, intramolecular cyclization and other reactions. After that, bromine atoms are introduced through the formation of stable lactone structure, followed by aminolysis, oxidation and intramolecular cyclization to form a ring containing semi acetaldehyde, a single isomer (-) - amathaspiramide F is obtained. Chapter 3 depicts the asymmetric synthesis of the alkaloid (-)-cephalotaxine. (-)-Cephalotaxine has three contiguous stereocenters and does not have pharmacological activity. Homoharringtonine is the ester of (-)-cephalotaxine, which has anti-tumor activity and has been approved by the FDA for treating chronic myeloid leukemia. Since the separation, there have been many studies on the total synthesis of (-)-cephalotaxine, few studies on the total synthesis are accomplished by asymmetric catalysis. We applied Ir/Cu synergistic catalysis to the asymmetric synthesis of the alkaloid (-)-cephalotaxine, constructing vicinal stereocenters in one step. Subsequently, the D ring was constructed by RCM reaction, and then the C ring was constructed by several transformation steps and oxidation state adjustment. Finally, using reductive amination, an intramolecular Friedel reaction occurs under acidic conditions, closing the seven-membered ring, and obtaining the intermediate of Mori route After three steps of transformation, the formal synthesis of (-)-cephalotaxine was completed.
语种	中文
	2022-11
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/151853/75224
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	李路路. 生物碱(-)-Amathaspiramide F和(-)-Cephalotaxine 的不对称合成[D]. 中国科学院大学,2022.

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